* 601007

LEPTIN RECEPTOR; LEPR


Alternative titles; symbols

OBR


HGNC Approved Gene Symbol: LEPR

Cytogenetic location: 1p31.3     Genomic coordinates (GRCh38): 1:65,420,652-65,641,559 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p31.3 Obesity, morbid, due to leptin receptor deficiency 614963 AR 3

TEXT

Description

Leptin (LEP; 164160), an adipocyte-specific hormone that regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure, acts through the leptin receptor (LEPR), a single-transmembrane-domain receptor of the cytokine receptor family.


Cloning and Expression

The OB gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, Tartaglia et al. (1995) generated a series of leptin-alkaline phosphatase fusion proteins, as well as (125I)-leptin. After a binding survey of cell lines and tissues, they identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened for a leptin-alkaline phosphatase fusion protein to identify a leptin receptor, OBR. OBR is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor (147880), the GCSF receptor (138971), and the LIF receptor (151443). OBR mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping demonstrated that the Obr gene is located on mouse chromosome 4 in a 5.1-cM interval that contains the well-characterized recessive obesity mutation, diabetes (db), which like the ob mutation, results in profound and early-onset obesity.

The phenotype of db/db mice is nearly identical to that of ob/ob mice (Coleman, 1978). Parabiosis studies with ob/ob and db/db mice indicated that db/db mice may be defective in reception of the ob gene product signal (Coleman, 1973). These data led to speculation that the db gene may encode the receptor for leptin, although the findings would also be consistent with db encoding a component of the leptin signal transduction pathway. However, Tartaglia et al. (1995) found that (125I) leptin and the AP-OB fusion protein bind nearly as well to the choroid plexus of db/db mice as to that of wildtype mice. Furthermore, they did not identify a mutation within the coding sequence of the mRNA species expressed in the choroid plexus of these mice. Therefore, they concluded that, if the db gene encodes Obr, it is likely that the mutation in this allele will be found in a different splice variant of the mouse Obr, such as a splice form similar to the human brain OBR homolog which they identified. They isolated and sequenced a cDNA clone hybridizing to OBR from a human infant total brain cDNA. The amino acid sequences from mouse and human were highly homologous throughout the length of the mouse protein; however, they found that the human cDNA encoded a protein with a much longer intracellular domain than mouse Obr.

Takaya et al. (1996) cloned the full-length rat leptin receptor and identified 3 alternatively spliced isoforms, Ob-Ra, Ob-Rb, and Ob-Re. While Ob-Ra and Ob-Rb predict single transmembrane proteins, Ob-Re is a soluble form of the receptor.


Gene Structure

Chung et al. (1996) defined the boundaries of the 18 coding exons for the long form of OBR and sequenced the immediately adjacent intronic regions. They also identified 2 highly polymorphic intronic microsatellites that could be scored by PCR.


Mapping

By genetic mapping, Tartaglia et al. (1995) demonstrated that the Obr gene is located on mouse chromosome 4, in a 5.1-cM interval that contains the well-characterized recessive obesity mutation, diabetes (db). Chung et al. (1996) developed a genetic map of 1p in the region of the OBR gene. They mapped the OBR gene physically by radiation hybrid mapping and placed it on a contig composed of 10 adjacent YACs and 5 P1 artificial chromosomes (PACs). The location of the human homolog of Obr was predicted to be on 1p based on conserved linkage of most of the telomeric half of mouse chromosome 4 with human 1p. Although OBR maps to 1p, Chung et al. (1996) described an apparent rearrangement of the order of genes in humans relative to that observed in mice and rats. They found that OBR1 is located on the centromeric side of PGM1 (171900), which is located at 1p31. JUN (165160) and C8B (120960), which map to 1p32-p31 and 1p32, respectively, were found to be located further telomeric of PGM1.

Winick et al. (1996) mapped the leptin receptor gene to chromosome 1 by PCR analysis of the segregation of the human gene in DNA samples from a panel of human/hamster somatic cell hybrids retaining different human chromosomes. The OBR gene was further regionalized by linkage studies approximately 3 to 4 cM distal to microsatellite marker D1S515 at chromosome position 1p31. The assignment was predicted by the map position of db on chromosome 4 in the mouse. Further observations indicated to Winick et al. (1996) that the human OBR gene is transcribed 5-prime to 3-prime toward the centromere.


Gene Function

The leptin receptor is found in many tissues in several alternatively spliced forms, raising the possibility that leptin exerts effects on many tissues including the hypothalamus. The leptin receptor is a member of the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins (see 600555). In order to identify the sites of leptin action in vivo, Vaisse et al. (1996) assayed for activation of STAT proteins in mice treated with leptin. The STAT proteins bind to phosphotyrosine residues in the cytoplasmic domain of the ligand-activated receptor, where they are subsequently phosphorylated. The activated STAT proteins dimerize and translocate to the nucleus where they bind DNA and activate transcription. The investigators assayed the activation of STAT proteins in response to leptin in a variety of mouse tissues known to express Obr. Leptin injection activated Stat3 (102582) but no other STAT protein in the hypothalamus of ob/ob and wildtype mice but not db/db mice, mutants that lack an isoform of the leptin receptor. Leptin did not induce STAT activation in any of the other tissues tested. The dose-dependent activation of STAT3 by leptin was first observed after 15 minutes and maximal in 30 minutes. The data indicated to Vaisse et al. (1996) that the hypothalamus is a direct target of leptin action and this activation is critically dependent on the gp130-like leptin receptor isoform missing in db/db mice.

Ghilardi et al. (1996) cloned a long isoform of the wildtype leptin receptor that is preferentially expressed in the hypothalamus and showed that it can activate signal transducer and activator of transcription (STAT) proteins STAT3, STAT5 (601511), and STAT6 (601512). A point mutation within the Obr gene of 'diabetic' (db) mice generated a new splice donor site that dramatically reduced expression of this long isoform in homozygous db/db mice. In contrast, an Obr protein with a shorter cytoplasmic domain was present in both db/db and wildtype mice. Ghilardi et al. (1996) showed that the short isoform is unable to activate the STAT pathway. The data provided further evidence that the mutation in the 'obese' receptor causes the db/db phenotype and identified 3 STAT proteins as potential mediators of the anti-obesity effects of leptin. Darnell (1996) stated that 6 mouse and human STATs were known (or 7, if the duplicated STAT5A and STAT5B genes were considered as 2); at least STAT1 (600555), STAT3, and STAT5 exhibit differentially spliced forms. Over 30 different polypeptides have been recorded that cause STAT activation in various mammalian cells. In the experiments of Ghilardi et al. (1996), STAT1, STAT2 (600556), and STAT4 (600558) were not detectably activated. Darnell (1996) observed that it will be crucial to show whether the set of STATs (3, 5, and 6) is activated by leptin in the hypothalamus, which is hypothesized to be the center for weight control in the Coleman model (Coleman, 1978). In this model, the ob gene product, a circulating hormone now identified as leptin, would operate by binding to a hypothalamic receptor, the db gene product, to regulate feeding. Darnell (1996) stated that, based on the homology between the leptin receptor and the gp130 transmembrane protein (JAK3; 600173), the pathway through which the leptin receptor seems likely to signal is the JAK/STAT pathway.

See Gloaguen et al. (1997) for discussion of the effects of ciliary neurotropic factor (CNTF; 118945) administration to both db/db and ob/ob mice.

Considine et al. (1996) examined expression of the OBR gene in hypothalamic tissue from lean and obese humans. The tissue was obtained shortly after autopsy in the Washington, D.C. Medical Examiner's Office. There was no difference in the amount of leptin-receptor mRNA in 7 lean and 8 obese subjects as determined by RT-PCR. A sequence polymorphism (A-to-G) was detected at nucleotide 668 of the leptin receptor cDNA (601007.0001). The occurrence of the polymorphic allele(s) did not correlate with the body mass index in the patients studied. Neither the mutation in the leptin receptor gene found in db/db mice nor that found in fa/fa rat were found in the human obese cases. The results suggested that leptin resistance observed in obese humans is not due to a defect in the leptin receptor.

The peripheral production of leptin by adipose tissue and its putative effect as a signal of satiety in the CNS suggest that leptin gains access to the regions of the brain regulating energy balance by crossing the brain capillary endothelium, which constitutes the blood-brain barrier in vivo. Golden et al. (1997) found from study of the binding and internalization of mouse recombinant leptin in isolated human brain capillaries that the leptin receptor mediates saturable, specific, temperature-dependent binding and endocytosis of leptin at the human blood-brain barrier.

Sierra-Honigmann et al. (1998) demonstrated that the leptin receptor, although expressed primarily in the hypothalamus, is also expressed in human vasculature and in primary cultures of human endothelial cells. In vitro and in vivo assays revealed that leptin has angiogenic activity. In vivo, leptin induced neovascularization in corneas from normal rats but not in corneas from fa/fa Zucker rats, which lack functional leptin receptors. These observations indicated that the vascular endothelium is a target for leptin and suggested a physiologic mechanism whereby leptin-induced angiogenesis may facilitate increased energy expenditure.

Bardet-Biedl syndrome (BBS; 209900) is genetically heterogeneous obesity syndrome associated with ciliary dysfunction. BBS proteins are thought to play a role in cilia function and intracellular protein/vesicle trafficking. Seo et al. (2009) showed that BBS proteins were required for Lepr signaling in the hypothalamus in mice. Bbs2 (606151) -/-, Bbs4 (600374) -/-, and Bbs6 (MKKS; 604896) -/- mice were resistant to the action of leptin to reduce body weight and food intake regardless of serum leptin levels and obesity. Activation of hypothalamic Stat3 by leptin was significantly decreased in Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice. In contrast, downstream melanocortin receptor (see 155555) signaling was unaffected, indicating that Lepr signaling was specifically impaired in Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice. Impaired Lepr signaling in BBS mice was associated with decreased Pomc (176830) gene expression. The human BBS1 (209901) protein physically interacted with LEPR, and loss of BBS proteins perturbed LEPR trafficking in human cells. Seo et al. (2009) concluded that BBS proteins mediate LEPR trafficking and that impaired LEPR signaling may underlie energy imbalance in BBS.

Using Scf(gfp) knockin mice, Ding et al. (2012) found that stem cell factor (SCF; 184745) was primarily expressed by perivascular cells throughout the bone marrow. Hematopoietic stem cell (HSC) frequency and function were not affected when Scf was conditionally deleted from hematopoietic cells, osteoblasts, or nestin-cre- or nestin-creER-expressing cells. However, HSCs were depleted from bone marrow when Scf was deleted from endothelial cells or Lepr-expressing perivascular stromal cells. Most HSCs were lost when Scf was deleted from both endothelial and Lepr-expressing perivascular cells. Ding et al. (2012) concluded that HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance.

Amebiasis caused by the enteric protozoan parasite Entamoeba histolytica can manifest as asymptomatic colonization, noninvasive diarrhea, dysentery, and extraintestinal infection, including liver abscess, and results in approximately 100,000 deaths worldwide per year. Using an in vitro model with human cells, Marie et al. (2012) showed that expression of LPR conferred increased resistance to amebic cytotoxicity, including CASP3 (600636) activation. The resistance depended on activation of STAT3, but not SHP2 (PTPN11; 176876) or STAT5. The gln223-to-arg (Q223R; 601007.0001) polymorphism in LPR increased susceptibility to amebic cytotoxicity and decreased leptin-dependent STAT3 activation. The authors found that apoptotic genes, including TRIB1 (609461) and SOCS3 (604176), which have opposing roles in apoptosis regulation, were highly enriched in a subset of genes uniquely regulated by STAT3 in response to leptin. Marie et al. (2012) concluded that the LPR-STAT3 signaling pathway restricts amebic pathogenesis and reveals a link between nutrition and susceptibility to infection.

By combining whole-mount confocal immunofluorescence imaging techniques and computational modeling to analyze significant 3-dimensional associations in the mouse bone marrow among vascular structures, stromal cells, and hematopoietic stem cells (HSCs), Kunisaki et al. (2013) showed that quiescent HSCs associate specifically with small arterioles that are preferentially found in endosteal bone marrow. These arterioles are ensheathed exclusively by rare NG2 (CSPG4; 601172)-positive pericytes, distinct from sinusoid-associated LEPR-positive cells. Pharmacologic or genetic activation of the hematopoietic stem cell cycle alters the distribution of HSCs from NG2-positive periarteriolar niches to LEPR-positive perisinusoidal niches. Conditional depletion of NG2-positive cells induces HSC cycling and reduces functional long-term repopulating HSCs in the bone marrow. Kunisaki et al. (2013) concluded that arteriolar niches are indispensable for maintaining HSC quiescence.


Molecular Genetics

Leptin Receptor Deficiency

Clement et al. (1998) reported a mutation in the human leptin receptor gene (601007.0002), a G-to-A transition at the +1 position of intron 16, that causes obesity and pituitary dysfunction (LEPRD; 614963). The mutation was discovered in homozygosity in a consanguineous family of Kabylian (Berber of northern Algeria) origin in which 3 of 9 sibs had morbid obesity with onset in early childhood. In addition to obesity, the homozygous sibs had no pubertal development and reduced secretion of growth hormone (139250) and thyrotropin (see 188540). Clement et al. (1998) considered their results to indicate that leptin is an important physiologic regulator of several endocrine functions in humans.

To determine the prevalence of pathogenic LEPR mutations in severely obese patients, Farooqi et al. (2007) sequenced LEPR in 300 patients with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families. Eight (3%) of the 300 patients had nonsense or missense LEPR mutations, including 7 homozygotes and 1 compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected individuals were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these patients. Their clinical features were less severe than those of patients with congenital leptin deficiency.

In a consanguineous Iranian family in which 9 members had severe early-onset obesity mapping to chromosome 1p31.3, Dehghani et al. (2018) sequenced the LEPR gene and identified homozygosity for a nonsense mutation (Y155X; 601007.0006). The mutation segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, gnomAD, GME Variome Project, or Iranome databases.

LEPR Polymorphism and Relation to Obesity-Related Phenotypes

Gotoda et al. (1997) determined the entire coding sequence of the human leptin receptor cDNA from peripheral blood lymphocytes of 22 morbidly obese patients with body-mass index (BMI) between 35.1 and 60.9 kg/m(2). They identified 5 common DNA sequence variants distributed throughout the coding sequence at codons 109, 223, 343, 656, and 1019, 1 rare silent mutation at codon 986, and 1 novel alternatively spliced form of transcript. None of the 5 common variants, including the 3 that predict amino acid changes, were null mutations causing morbid obesity, because homozygotes for the variant sequences were also found in lean subjects. Furthermore, the frequency of each variant allele and the distribution of genotypes and haplotypes were similar in 190 obese and 132 lean white British males selected from a population-based epidemiologic survey. Gotoda et al. (1997) suggested that mutations in the leptin receptor gene are not a common cause of human obesity.

Rosmond et al. (2000) studied the possible role of the leptin receptor on regulation of blood pressure. Two hundred eighty-four 51-year-old men were selected, and anthropometric, endocrine, metabolic, and hemodynamic variables were examined in relation to LEPR polymorphisms by RFLP analysis. Three polymorphisms were examined: lys109 to arg in exon 4, gln223 to arg in exon 6 (601007.0001), and lys656 to asn in exon 14. In comparison with lys109 homozygotes, arg109 homozygotes (9%) showed lower BMI and abdominal sagittal diameter, as well as lower systolic and diastolic blood pressure. Additionally, arg223 homozygotes (26.8%) showed lower blood pressure than gln223 homozygotes. These lower blood pressure levels were independent of other variables. No differences were found with the lys656-to-asn polymorphism. Measurements of body fat mass correlated with leptin concentration in lys109 homozygotes and in lys109 heterozygotes, but not in arg109 homozygotes. Blood pressure correlated with leptin only in men carrying the wildtype allele lys109. The authors concluded that leptin is associated with blood pressure regulation in men through the leptin receptor. When BMI and leptin are elevated, increased blood pressure is found only with the most prevalent LEPR genotype at codons 109 and 223, whereas variants of this receptor seem to protect from hypertension.

Yiannakouris et al. (2001) evaluated a genetically homogeneous Greek population for associations between body composition variables and 3 common LEPR gene polymorphisms (K109R, Q223R (601007.0001), and K656N) that have potential functional significance and assessed the contributions of these polymorphisms to the variability of obesity. For the Q223R polymorphism, there was a higher prevalence of the R223 allele in the homozygous form among overweight-obese subjects versus normal weight subjects (20.7% vs 4.5%; P = 0.01). Furthermore, simple and multiple regression analyses revealed that the R223 allele in the homozygous form is a significant predictor of both BMI (P = 0.015) and percent fat mass (P = 0.02) even after adjusting for age and gender and explains 4.5% of the variance in percent fat mass and 5% of the variance in BMI. There was no significant difference in allele frequencies or genotype distributions for the K109R or K656N polymorphisms. These findings support the hypothesis that the Q223R polymorphism, but not the K109R or K656N polymorphism, of LEPR is associated with obesity and predicts a small percentage of body weight and body composition variability in a genetically homogeneous population.

Wauters et al. (2001) investigated the relationship between LEPR polymorphisms and glucose and insulin (176730) response to an oral glucose tolerance test (OGTT). Three LEPR polymorphisms (K109R, 601007.0004; Q223R, 601007.0001; and K656N, 601007.0005;) were typed on genomic DNA of 358 overweight and obese women, aged 18 to 60 years. Based on an OGTT, 269 subjects were defined with normal glucose tolerance, and 89 with impaired glucose tolerance. In 24 postmenopausal women with impaired glucose tolerance, associations were found with K109R and K656N for fasting insulin (P = 0.05) and with K109R and Q223R for the insulin response to an OGTT (P less than 0.02). In the same group, trends were found with K656N for fasting glucose as well as in response to the OGTT. In 65 premenopausal women with impaired glucose tolerance, associations were found with K109R and K656N for overall glucose response to the glucose load. In contrast, no associations with insulin or glucose were found in women with normal glucose tolerance. The authors concluded that LEPR polymorphisms are associated with insulin and glucose metabolism in women with impaired glucose homeostasis.

Park et al. (2006) genotyped 11 polymorphisms of the LEPR gene in 775 unrelated Korean patients with type II diabetes and 688 controls. No significant associations between the polymorphisms and the risk of type II diabetes were detected, but the K109R SNP, which they called R109K, showed marginal association with BMI (p = 0.02) and gene dose-dependent effects were observed.

Sun et al. (2010) conducted a genomewide association study of plasma soluble leptin receptor (sOB-R) levels in 1,504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single-nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels, all mapping to LEPR. Analysis of imputed genotypes on autosomal chromosomes revealed an additional 106 SNPs in and adjacent to this gene that reached genomewide significance level. Of these 132 SNPs (including 2 nonsynonymous SNPs, rs1137100 and rs1137101), rs2767485, rs1751492 and rs4655555 remained associated with sOB-R levels at the 0.05 level after adjustment for other univariately associated SNPs in a forward selection procedure. Significant associations with these SNPs were replicated in an independent sample of 875 young males residing in Cyprus.


Animal Model

Takaya et al. (1996) identified a mutation in Obr in Zucker fatty (fa/fa) rats, a missense mutation (an A-to-C conversion at nucleotide position 806) in the extracellular domain of all the isoforms that results in a single amino acid change from gln to pro at position 269. Chua et al. (1996) showed by genetic mapping and genomic analysis that mutations in the mouse and rat leptin receptors account for the mouse diabetes (db) and rat fatty (fa) phenotypes, respectively. Lee et al. (1996) likewise found that mutation in the leptin receptor gene results in db mice. They showed that the murine receptor has at least 6 alternatively spliced forms, 1 of which is expressed at a high level in the hypothalamus and is spliced abnormally in db/db mice. From their studies, Lee et al. (1996) also concluded that abnormal splicing of the Obr mRNA resulted in a mutant protein lacking the cytoplasmic region. Chen et al. (1996) identified an alternatively spliced transcript that encodes a form of mouse Obr with a long intracellular domain. They found that db/db mice also produced this alternatively spliced transcript, but with a 106-bp insertion that prematurely terminates the intracellular domain. They identified a G-to-T transversion in the genomic Obr sequence in these mice. This mutation generates a donor splice site that converts the 106-bp region to a novel exon retained in the Obr transcript. They predicted that the long intracellular domain form of the receptor is crucial for initiating intracellular signal transduction, and as a corollary, the inability to produce this form of Obr leads to the severe obesity phenotype found in db/db mice.

The obese spontaneously hypertensive Koletsky rat strain develop obesity, hyperlipidemia, hyperinsulinemia, and proteinuria with kidney disease, which were thought to be due to a single recessive gene. Breeding data from crosses of the Zucker rat and the Koletsky rat suggested that alleles at the same locus may be responsible for the obese phenotype of these strains. This was proved to be the case by Takaya et al. (1996) who found a nonsense mutation in the leptin receptor gene in the Koletsky rat. Thus the fa/fa (Zucker) rat and the Koletsky rat both have mutations in the leptin receptor, as does the db/db mouse.

Ducy et al. (2000) studied ob/ob and db/db mice, which were obese and hypogonadic. Both mutant mice had increased bone formation, leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype was dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There was no leptin signaling in osteoblasts, but intracerebroventricular infusion of leptin caused bone loss in leptin-deficient and wildtype mice. This study identified leptin as a potent inhibitor of bone formation acting through the central nervous system.

Cohen et al. (2001) generated mice with neuron- and hepatocyte-specific conditional deletion of Lepr. Neuron-specific Lepr-null mice with the lowest levels of hypothalamic Lepr exhibited an obese phenotype, and these obese null mice had elevated plasma levels of leptin, glucose, insulin, and corticosterone, as well as increased hypothalamic agouti-related protein (AGRP; 602311) and neuropeptide Y (NPY; 162640) RNA. Hepatocyte-specific Lepr-null mice weighed the same as controls and had no alterations in body composition. In addition, db/db mice and neuron-specific Lepr-null mice had enlarged fatty livers, whereas the hepatocyte-specific Lepr-null mice did not. Cohen et al. (2001) suggested that the brain is a direct target for the weight-reducing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain.

Balthasar et al. (2004) generated mice with conditional deletion of leptin receptors on proopiomelanocortin (POMC; 176830) neurons and observed mild obesity, hyperleptinemia, and altered expression of hypothalamic neuropeptides. Because the body weight increase was only 18% of that seen in mice with complete deficiency of leptin receptors, the authors concluded that leptin receptors on POMC neurons are required but not solely responsible for leptin's regulation of body weight homeostasis.

Tian et al. (2002) found that the percentage and total number of natural killer (NK) cells in lymphoid organs and peripheral blood were reduced in Lepr-deficient mice. Furthermore, NK cell activation and target cell lysis were retarded in these mice.

Tyr1138 of the leptin receptor long form (LRb) mediates activation of the transcription factor STAT3 (102582) during leptin action. To investigate the contribution of STAT3 signaling to leptin action in vivo, Bates et al. (2003) replaced the gene encoding the leptin receptor (Lepr) in mice with an allele coding for replacement of tyr1138 in LRb with a serine residue that specifically disrupts the LRb-STAT3 signal. Like db/db mice, Lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short, and diabetic, s/s mice are fertile, long, and less hyperglycemic. Furthermore, hypothalamic expression of Npy is elevated in db/db mice but not in s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. Bates et al. (2003) concluded that LRb-STAT3 signaling mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth, and glucose homeostasis.

Bjornholm et al. (2007) showed that mice homozygous for a tyr985-to-leu mutation in LRb were neuroendocrinologically normal but that females demonstrated decreased feeding, decreased expression of orexigenic neuropeptides, protection from high-fat-diet-induced obesity, and increased leptin sensitivity in a sex-biased manner. The authors concluded that leptin activates autoinhibitory signals via LRb tyr985 to attenuate the antiadiposity effects of leptin, especially in females, which may contribute to leptin insensitivity in obesity.

Kaneto et al. (2004) developed a cell-permeable JNK1 (601158) inhibitory peptide. Intraperitoneal administration of the peptide led to its transduction in various tissues in vivo, and this treatment markedly improved insulin resistance and ameliorated glucose tolerance in db/db diabetic mice. Kaneto et al. (2004) concluded that the JNK pathway is critically involved in diabetes and that the cell-permeable JNK inhibitory peptide may have promise as a therapeutic agent for diabetes.

Zhang et al. (2004) selectively deleted tyrosine phosphatase Shp2 (176876) in postmitotic forebrain neurons of mice and observed the development of early-onset obesity with increased serum levels of leptin, insulin, glucose, and triglycerides, although the mutant mice were not hyperphagic. In wildtype mice, the authors found that Shp2 downregulation of Jak2 (147796)/Stat3 activation by leptin (164160) in the hypothalamus was offset by a dominant Shp2 promotion of the leptin-stimulated Erk (see 601795) pathway; thus, Shp2 deletion in the brain results in induction rather than suppression of leptin resistance. Zhang et al. (2004) suggested that a primary function of SHP2 in the postmitotic forebrain is to control energy balance and metabolism, and that SHP2 is a critical signaling component of the leptin receptor in the hypothalamus.

In Koletsky fa(k)/fa(k) (LEPR-null) rats, Morton et al. (2005) observed markedly increased meal size and reduced satiety in response to cholecystokinin (CCK; 118440), suggesting a role for leptin signaling in the response to endogenous signals that promote meal termination. Restoration of LEPR in the area of the hypothalamic arcuate nucleus of fa(k)/fa(k) rats by adenoviral gene therapy normalized the effect of CCK on the activation of neurons in key hindbrain areas for processing satiety signals and also reduced meal size and enhanced CCK-induced satiety. Morton et al. (2005) concluded that forebrain signaling by leptin limits food intake on a meal-to-meal basis by regulating the hindbrain response to short-acting satiety signals.

In mouse models of type II diabetes, either Irs2 -/- (600797) or Lepr -/- (db/db), Uchida et al. (2005) observed progressive accumulation of p27 (CDKN1B; 600778) in the nucleus of pancreatic beta cells. Deletion of Cdkn1b ameliorated hyperglycemia by increasing islet mass and maintaining compensatory hyperinsulinemia, which the authors attributed predominantly to stimulation of pancreatic beta-cell proliferation. Uchida et al. (2005) concluded that p27 contributes to beta-cell failure in the development of type II diabetes in Irs2 -/- and db/db mice.

De Luca et al. (2005) generated db/db mice that were compound hemizygotes for both of the neuron-specific transgenes, synapsin (313440)-Lepr-B and Eno2 (131360)-Lepr-B, and observed complete correction of the obesity and related phenotypes: body composition, insulin sensitivity, cold tolerance, expression of 3 neuropeptide genes (Agrp, Npy, and Pomc), and fertility were fully normalized in the dual transgenic db/db mice. De Luca et al. (2005) concluded that brain-specific signaling is sufficient to reverse the obesity, diabetes, and fertility of db/db mice.

Using in situ peroxidase and immunofluorescence staining in mouse hearts, Raju et al. (2006) localized Cntf receptors (CNTFR; 118946) to the sarcolemma and confirmed the localization by immunoblot on isolated myocytes. Subcutaneous administration of recombinant CNTF (118945) in ob/ob and db/db mice resulted in significant reductions in cardiac hypertrophy. Western blotting showed that both leptin and CNTF activated STAT3 and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) pathways in cultured adult mouse cardiomyocytes and cardiac tissue from ob/ob and db/db mice. Raju et al. (2006) concluded that CNTF plays a role in a cardiac signal transduction pathway that regulates obesity-related left ventricular hypertrophy.

Morioka et al. (2007) generated pancreas-specific Lepr -/- mice and observed improved glucose tolerance due to enhanced early-phase insulin secretion and a greater beta-cell mass secondary to increased beta-cell size and enhanced expression and phosphorylation of p70S6K (RPS6KB1; 608938). Challenging the knockout mice with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Morioka et al. (2007) concluded that leptin plays a critical signaling role in islet biology and suggested that altered leptin action in islets is a factor that contributes to obesity-associated diabetes.

Czupryn et al. (2011) generated physically chimeric hypothalami by microtransplanting small numbers of embryonic enhanced green fluorescent protein-expressing leptin-responsive hypothalamic cells into hypothalami of postnatal Lepr-deficient (db/db) mice, which develop morbid obesity. Donor neurons differentiated and integrated as 4 distinct hypothalamic neuron subtypes, formed functional excitatory and inhibitory synapses, partially restored leptin responsiveness, and ameliorated hyperglycemia and obesity in db/db mice. Czupryn et al. (2011) concluded that their experiments served as a proof of concept that transplanted neurons can functionally reconstitute complex neuronal circuitry in the mammalian brain.


ALLELIC VARIANTS ( 6 Selected Examples):

.0001 LEPTIN RECEPTOR POLYMORPHISM

LEPR, GLN223ARG
  
RCV000009047...

In hypothalamic tissue from lean and obese humans obtained shortly after autopsy in the Washington, D.C. Medical Examiner's Office, Considine et al. (1996) detected an A-to-G sequence polymorphism at nucleotide 668 of the leptin receptor cDNA. This base substitution changed a glutamine to an arginine at position 23 of the leptin receptor protein. Of 15 subjects analyzed, 11 were heterozygous for this base change and 3 were homozygous. There was no difference in the amount of leptin-receptor mRNA in 7 lean and 8 obese subjects as determined by RT-PCR. The occurrence of the polymorphic allele(s) did not correlate with the body mass index in the patients studied. The results suggested that leptin resistance observed in obese humans is not due to a defect in the leptin receptor.

An A/G single-nucleotide polymorphism in the LEPR gene is associated with a gln223-to-arg (Q223R) amino acid polymorphism. Thompson et al. (1997) found that homozygosity for the G allele is associated with lower plasma leptin levels after correction for obesity, gender, and family. Quinton et al. (2001) sought to determine whether similar associations could be observed in Caucasians by studying a community-based population of postmenopausal women in the Sheffield area of the U.K. They found that genotypes at that locus are associated with differences in body mass index, fat mass, and serum leptin levels. Measurement of serum leptin-binding activity indicated that this may reflect changed receptor function associated with genotype.

In a group of postmenopausal women with impaired glucose tolerance, Wauters et al. (2001) found an association of the Q223R polymorphism with insulin response to an oral glucose tolerance test.

Richert et al. (2007) investigated the association of the Q223R polymorphism in the LEPR gene with bone mineral content and areal bone mineral density in prepubertal boys. LEPR genotypes were significantly associated with baseline bone mineral content at the hip (p = 0.017), femur diaphysis (p = 0.019), and radius (p = 0.007), and with height (p = 0.041) as well as with physical activity (p = 0.016). On average, bone mineral content was 8 to 12% lower in arg/arg than in gln/gln carriers, with gln/arg carriers having intermediate values. Associations with height and bone mineral content at femur diaphysis and radius remained significant after 2 years. Significant differences in 2-year bone mass gain at the spine and femur neck were also found among LEPR genotypes. Richert et al. (2007) concluded that the LEPR Q223R polymorphism was associated with bone mass in growing boys. The association, however, was markedly dependent on bone area, body size, and physical activity, in addition to VDR genetic variation, suggesting that the leptin system may modulate bone mass in humans mostly through indirect mechanisms.

Amebiasis, a potentially fatal enteric infection caused by the parasite Entamoeba histolytica, is exacerbated by malnutrition. Duggal et al. (2011) prospectively observed a cohort of Bangladeshi children for 9 years beginning at preschool age for E. histolytica infection and evaluated them for LEPR variants. They found that children carrying the 223R allele of the Q223R polymorphism had 4-fold increased susceptibility to intestinal infection compared with those homozygous for 223Q. Examination of an independent cohort of adult patients showed that those carrying the 223R allele had increased risk of amebic liver abscess. Mice with at least 1 copy of the R allele were more susceptible to amebic infection and exhibited greater levels of mucosal destruction, as well as intestinal epithelial apoptosis, after infection. Duggal et al. (2011) proposed that leptin signaling is important in mucosal defense against amebiasis and that LPR polymorphisms explain differences in susceptibility of children to amebiasis.

Using human cells, Marie et al. (2012) showed that the Q223R polymorphism in LPR increased susceptibility to amebic cytotoxicity and decreased leptin-dependent STAT3 (102582) activation.


.0002 LEPTIN RECEPTOR DEFICIENCY

LEPR, IVS16DS, G-A, +1
  
RCV000009048

In a consanguineous family of Kabylian (Berber of northern Algeria) origin in which 3 of 9 sibs had morbid obesity with onset in early childhood (LEPRD; 614963), Clement et al. (1998) detected homozygosity for a G-to-A transition at the +1 position of intron 16 of the LEPR gene, causing obesity and pituitary dysfunction. The splice site mutation results in skipping of exon 16, which leads to a truncated protein of 831 amino acids lacking both the transmembrane and intracellular domains.


.0003 REMOVED FROM DATABASE


.0004 LEPTIN RECEPTOR POLYMORPHISM

LEPR, LYS109ARG
  
RCV000009049...

In a study of the relationship between LEPR polymorphisms and glucose and insulin response to an oral glucose tolerance test, Wauters et al. (2001) found an association in postmenopausal women with impaired glucose tolerance of the lys109-to-arg (K109R) polymorphism in exon 3 of the LEPR gene with fasting insulin, and of K109R with the insulin response to an oral glucose tolerance test. In premenopausal women with impaired glucose tolerance, they found an association of K109R with overall glucose response to the glucose load.


.0005 LEPTIN RECEPTOR POLYMORPHISM

LEPR, LYS656ASN
  
RCV000009050...

In a study of the relationship between LEPR polymorphisms and glucose and insulin response to an oral glucose tolerance test, Wauters et al. (2001) found an association in postmenopausal women with impaired glucose tolerance of the lys656-to-asn (K656N) polymorphism with fasting insulin. In the same group, they found a trend with K656N for fasting glucose as well as in response to the oral glucose tolerance test. In premenopausal women with impaired glucose tolerance, they found an association of K656N with overall glucose response to the glucose load.


.0006 LEPTIN RECEPTOR DEFICIENCY

LEPR, TYR155TER
  
RCV000760143

In a consanguineous Iranian family in which 9 members had severe early-onset obesity (LEPRD; 614963) mapping to chromosome 1p31.3, Dehghani et al. (2018) sequenced the LEPR gene and identified homozygosity for a c.464T-G transversion (c.464T-G, NM_002303.5) in exon 3, resulting in a tyr155-to-ter (Y155X) substitution. The mutation affects the extracellular N terminus, thus impacting all transcripts, and is predicted to result in a complete loss of function due to nonsense-mediated decay. The mutation segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, gnomAD, GME Variome Project, or Iranome databases.


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Sonja A. Rasmussen - updated : 03/12/2019
Paul J. Converse - updated : 03/07/2016
Ada Hamosh - updated : 2/5/2014
Ada Hamosh - updated : 2/8/2012
Ada Hamosh - updated : 1/9/2012
George E. Tiller - updated : 12/1/2011
George E. Tiller - updated : 10/20/2009
Marla J. F. O'Neill - updated : 12/19/2008
John A. Phillips, III - updated : 6/24/2008
Marla J. F. O'Neill - updated : 11/5/2007
Marla J. F. O'Neill - updated : 10/24/2007
Victor A. McKusick - updated : 2/5/2007
Marla J. F. O'Neill - updated : 4/12/2006
Marla J. F. O'Neill - updated : 4/6/2006
Marla J. F. O'Neill - updated : 1/5/2006
Marla J. F. O'Neill - updated : 7/8/2005
Marla J. F. O'Neill - updated : 4/25/2005
Marla J. F. O'Neill - updated : 4/11/2005
Marla J. F. O'Neill - updated : 3/23/2005
Ada Hamosh - updated : 11/22/2004
Marla J. F. O'Neill - updated : 11/18/2004
Paul J. Converse - updated : 1/8/2004
Ada Hamosh - updated : 2/21/2003
John A. Phillips, III - updated : 3/5/2002
John A. Phillips, III - updated : 2/14/2002
John A. Phillips, III - updated : 10/1/2001
Victor A. McKusick - updated : 4/6/2001
Stylianos E. Antonarakis - updated : 2/8/2000
Victor A. McKusick - updated : 9/11/1998
Ada Hamosh - updated : 4/6/1998
Victor A. McKusick - updated : 8/25/1997
Victor A. McKusick - updated : 6/23/1997
Victor A. McKusick - updated : 3/4/1997
Victor A. McKusick - updated : 2/6/1997
Lori M. Kelman - updated : 12/6/1996
Alan F. Scott - updated : 2/15/1996
Creation Date:
Victor A. McKusick : 1/23/1996
carol : 05/01/2019
carol : 03/12/2019
carol : 09/15/2016
mgross : 03/07/2016
alopez : 11/10/2015
alopez : 2/5/2014
alopez : 2/5/2014
carol : 4/3/2013
alopez : 12/10/2012
alopez : 2/10/2012
terry : 2/8/2012
alopez : 1/9/2012
alopez : 12/6/2011
terry : 12/1/2011
alopez : 9/23/2010
mgross : 10/20/2009
wwang : 12/30/2008
terry : 12/19/2008
alopez : 6/24/2008
wwang : 11/14/2007
terry : 11/5/2007
wwang : 10/25/2007
terry : 10/24/2007
wwang : 2/7/2007
terry : 2/5/2007
alopez : 2/1/2007
wwang : 4/17/2006
terry : 4/12/2006
wwang : 4/7/2006
terry : 4/6/2006
wwang : 1/11/2006
terry : 1/5/2006
wwang : 7/20/2005
wwang : 7/15/2005
terry : 7/8/2005
wwang : 4/29/2005
wwang : 4/27/2005
terry : 4/25/2005
tkritzer : 4/13/2005
terry : 4/11/2005
terry : 4/5/2005
tkritzer : 3/23/2005
alopez : 12/2/2004
terry : 11/22/2004
tkritzer : 11/18/2004
mgross : 1/8/2004
cwells : 11/10/2003
joanna : 7/24/2003
alopez : 2/25/2003
terry : 2/21/2003
alopez : 3/5/2002
alopez : 2/14/2002
carol : 11/27/2001
alopez : 10/1/2001
cwells : 5/2/2001
mcapotos : 4/9/2001
terry : 4/6/2001
mgross : 2/8/2000
alopez : 9/13/1998
terry : 9/11/1998
terry : 9/11/1998
dkim : 9/10/1998
joanna : 5/15/1998
alopez : 4/6/1998
mark : 8/25/1997
alopez : 7/30/1997
mark : 7/8/1997
jenny : 6/23/1997
terry : 6/19/1997
jenny : 3/4/1997
terry : 2/24/1997
terry : 2/6/1997
terry : 1/24/1997
jamie : 1/21/1997
mark : 12/21/1996
terry : 12/16/1996
jamie : 12/6/1996
jenny : 12/6/1996
mark : 11/20/1996
terry : 11/14/1996
mark : 11/12/1996
terry : 11/4/1996
mark : 9/30/1996
terry : 9/26/1996
mark : 9/11/1996
terry : 9/11/1996
terry : 9/10/1996
terry : 9/9/1996
terry : 9/9/1996
terry : 9/3/1996
mark : 5/28/1996
terry : 4/17/1996
mark : 3/9/1996
terry : 3/4/1996
terry : 3/4/1996
mark : 2/15/1996
terry : 2/6/1996
mark : 1/23/1996

* 601007

LEPTIN RECEPTOR; LEPR


Alternative titles; symbols

OBR


HGNC Approved Gene Symbol: LEPR

Cytogenetic location: 1p31.3     Genomic coordinates (GRCh38): 1:65,420,652-65,641,559 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p31.3 Obesity, morbid, due to leptin receptor deficiency 614963 Autosomal recessive 3

TEXT

Description

Leptin (LEP; 164160), an adipocyte-specific hormone that regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure, acts through the leptin receptor (LEPR), a single-transmembrane-domain receptor of the cytokine receptor family.


Cloning and Expression

The OB gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, Tartaglia et al. (1995) generated a series of leptin-alkaline phosphatase fusion proteins, as well as (125I)-leptin. After a binding survey of cell lines and tissues, they identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened for a leptin-alkaline phosphatase fusion protein to identify a leptin receptor, OBR. OBR is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor (147880), the GCSF receptor (138971), and the LIF receptor (151443). OBR mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping demonstrated that the Obr gene is located on mouse chromosome 4 in a 5.1-cM interval that contains the well-characterized recessive obesity mutation, diabetes (db), which like the ob mutation, results in profound and early-onset obesity.

The phenotype of db/db mice is nearly identical to that of ob/ob mice (Coleman, 1978). Parabiosis studies with ob/ob and db/db mice indicated that db/db mice may be defective in reception of the ob gene product signal (Coleman, 1973). These data led to speculation that the db gene may encode the receptor for leptin, although the findings would also be consistent with db encoding a component of the leptin signal transduction pathway. However, Tartaglia et al. (1995) found that (125I) leptin and the AP-OB fusion protein bind nearly as well to the choroid plexus of db/db mice as to that of wildtype mice. Furthermore, they did not identify a mutation within the coding sequence of the mRNA species expressed in the choroid plexus of these mice. Therefore, they concluded that, if the db gene encodes Obr, it is likely that the mutation in this allele will be found in a different splice variant of the mouse Obr, such as a splice form similar to the human brain OBR homolog which they identified. They isolated and sequenced a cDNA clone hybridizing to OBR from a human infant total brain cDNA. The amino acid sequences from mouse and human were highly homologous throughout the length of the mouse protein; however, they found that the human cDNA encoded a protein with a much longer intracellular domain than mouse Obr.

Takaya et al. (1996) cloned the full-length rat leptin receptor and identified 3 alternatively spliced isoforms, Ob-Ra, Ob-Rb, and Ob-Re. While Ob-Ra and Ob-Rb predict single transmembrane proteins, Ob-Re is a soluble form of the receptor.


Gene Structure

Chung et al. (1996) defined the boundaries of the 18 coding exons for the long form of OBR and sequenced the immediately adjacent intronic regions. They also identified 2 highly polymorphic intronic microsatellites that could be scored by PCR.


Mapping

By genetic mapping, Tartaglia et al. (1995) demonstrated that the Obr gene is located on mouse chromosome 4, in a 5.1-cM interval that contains the well-characterized recessive obesity mutation, diabetes (db). Chung et al. (1996) developed a genetic map of 1p in the region of the OBR gene. They mapped the OBR gene physically by radiation hybrid mapping and placed it on a contig composed of 10 adjacent YACs and 5 P1 artificial chromosomes (PACs). The location of the human homolog of Obr was predicted to be on 1p based on conserved linkage of most of the telomeric half of mouse chromosome 4 with human 1p. Although OBR maps to 1p, Chung et al. (1996) described an apparent rearrangement of the order of genes in humans relative to that observed in mice and rats. They found that OBR1 is located on the centromeric side of PGM1 (171900), which is located at 1p31. JUN (165160) and C8B (120960), which map to 1p32-p31 and 1p32, respectively, were found to be located further telomeric of PGM1.

Winick et al. (1996) mapped the leptin receptor gene to chromosome 1 by PCR analysis of the segregation of the human gene in DNA samples from a panel of human/hamster somatic cell hybrids retaining different human chromosomes. The OBR gene was further regionalized by linkage studies approximately 3 to 4 cM distal to microsatellite marker D1S515 at chromosome position 1p31. The assignment was predicted by the map position of db on chromosome 4 in the mouse. Further observations indicated to Winick et al. (1996) that the human OBR gene is transcribed 5-prime to 3-prime toward the centromere.


Gene Function

The leptin receptor is found in many tissues in several alternatively spliced forms, raising the possibility that leptin exerts effects on many tissues including the hypothalamus. The leptin receptor is a member of the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins (see 600555). In order to identify the sites of leptin action in vivo, Vaisse et al. (1996) assayed for activation of STAT proteins in mice treated with leptin. The STAT proteins bind to phosphotyrosine residues in the cytoplasmic domain of the ligand-activated receptor, where they are subsequently phosphorylated. The activated STAT proteins dimerize and translocate to the nucleus where they bind DNA and activate transcription. The investigators assayed the activation of STAT proteins in response to leptin in a variety of mouse tissues known to express Obr. Leptin injection activated Stat3 (102582) but no other STAT protein in the hypothalamus of ob/ob and wildtype mice but not db/db mice, mutants that lack an isoform of the leptin receptor. Leptin did not induce STAT activation in any of the other tissues tested. The dose-dependent activation of STAT3 by leptin was first observed after 15 minutes and maximal in 30 minutes. The data indicated to Vaisse et al. (1996) that the hypothalamus is a direct target of leptin action and this activation is critically dependent on the gp130-like leptin receptor isoform missing in db/db mice.

Ghilardi et al. (1996) cloned a long isoform of the wildtype leptin receptor that is preferentially expressed in the hypothalamus and showed that it can activate signal transducer and activator of transcription (STAT) proteins STAT3, STAT5 (601511), and STAT6 (601512). A point mutation within the Obr gene of 'diabetic' (db) mice generated a new splice donor site that dramatically reduced expression of this long isoform in homozygous db/db mice. In contrast, an Obr protein with a shorter cytoplasmic domain was present in both db/db and wildtype mice. Ghilardi et al. (1996) showed that the short isoform is unable to activate the STAT pathway. The data provided further evidence that the mutation in the 'obese' receptor causes the db/db phenotype and identified 3 STAT proteins as potential mediators of the anti-obesity effects of leptin. Darnell (1996) stated that 6 mouse and human STATs were known (or 7, if the duplicated STAT5A and STAT5B genes were considered as 2); at least STAT1 (600555), STAT3, and STAT5 exhibit differentially spliced forms. Over 30 different polypeptides have been recorded that cause STAT activation in various mammalian cells. In the experiments of Ghilardi et al. (1996), STAT1, STAT2 (600556), and STAT4 (600558) were not detectably activated. Darnell (1996) observed that it will be crucial to show whether the set of STATs (3, 5, and 6) is activated by leptin in the hypothalamus, which is hypothesized to be the center for weight control in the Coleman model (Coleman, 1978). In this model, the ob gene product, a circulating hormone now identified as leptin, would operate by binding to a hypothalamic receptor, the db gene product, to regulate feeding. Darnell (1996) stated that, based on the homology between the leptin receptor and the gp130 transmembrane protein (JAK3; 600173), the pathway through which the leptin receptor seems likely to signal is the JAK/STAT pathway.

See Gloaguen et al. (1997) for discussion of the effects of ciliary neurotropic factor (CNTF; 118945) administration to both db/db and ob/ob mice.

Considine et al. (1996) examined expression of the OBR gene in hypothalamic tissue from lean and obese humans. The tissue was obtained shortly after autopsy in the Washington, D.C. Medical Examiner's Office. There was no difference in the amount of leptin-receptor mRNA in 7 lean and 8 obese subjects as determined by RT-PCR. A sequence polymorphism (A-to-G) was detected at nucleotide 668 of the leptin receptor cDNA (601007.0001). The occurrence of the polymorphic allele(s) did not correlate with the body mass index in the patients studied. Neither the mutation in the leptin receptor gene found in db/db mice nor that found in fa/fa rat were found in the human obese cases. The results suggested that leptin resistance observed in obese humans is not due to a defect in the leptin receptor.

The peripheral production of leptin by adipose tissue and its putative effect as a signal of satiety in the CNS suggest that leptin gains access to the regions of the brain regulating energy balance by crossing the brain capillary endothelium, which constitutes the blood-brain barrier in vivo. Golden et al. (1997) found from study of the binding and internalization of mouse recombinant leptin in isolated human brain capillaries that the leptin receptor mediates saturable, specific, temperature-dependent binding and endocytosis of leptin at the human blood-brain barrier.

Sierra-Honigmann et al. (1998) demonstrated that the leptin receptor, although expressed primarily in the hypothalamus, is also expressed in human vasculature and in primary cultures of human endothelial cells. In vitro and in vivo assays revealed that leptin has angiogenic activity. In vivo, leptin induced neovascularization in corneas from normal rats but not in corneas from fa/fa Zucker rats, which lack functional leptin receptors. These observations indicated that the vascular endothelium is a target for leptin and suggested a physiologic mechanism whereby leptin-induced angiogenesis may facilitate increased energy expenditure.

Bardet-Biedl syndrome (BBS; 209900) is genetically heterogeneous obesity syndrome associated with ciliary dysfunction. BBS proteins are thought to play a role in cilia function and intracellular protein/vesicle trafficking. Seo et al. (2009) showed that BBS proteins were required for Lepr signaling in the hypothalamus in mice. Bbs2 (606151) -/-, Bbs4 (600374) -/-, and Bbs6 (MKKS; 604896) -/- mice were resistant to the action of leptin to reduce body weight and food intake regardless of serum leptin levels and obesity. Activation of hypothalamic Stat3 by leptin was significantly decreased in Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice. In contrast, downstream melanocortin receptor (see 155555) signaling was unaffected, indicating that Lepr signaling was specifically impaired in Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice. Impaired Lepr signaling in BBS mice was associated with decreased Pomc (176830) gene expression. The human BBS1 (209901) protein physically interacted with LEPR, and loss of BBS proteins perturbed LEPR trafficking in human cells. Seo et al. (2009) concluded that BBS proteins mediate LEPR trafficking and that impaired LEPR signaling may underlie energy imbalance in BBS.

Using Scf(gfp) knockin mice, Ding et al. (2012) found that stem cell factor (SCF; 184745) was primarily expressed by perivascular cells throughout the bone marrow. Hematopoietic stem cell (HSC) frequency and function were not affected when Scf was conditionally deleted from hematopoietic cells, osteoblasts, or nestin-cre- or nestin-creER-expressing cells. However, HSCs were depleted from bone marrow when Scf was deleted from endothelial cells or Lepr-expressing perivascular stromal cells. Most HSCs were lost when Scf was deleted from both endothelial and Lepr-expressing perivascular cells. Ding et al. (2012) concluded that HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance.

Amebiasis caused by the enteric protozoan parasite Entamoeba histolytica can manifest as asymptomatic colonization, noninvasive diarrhea, dysentery, and extraintestinal infection, including liver abscess, and results in approximately 100,000 deaths worldwide per year. Using an in vitro model with human cells, Marie et al. (2012) showed that expression of LPR conferred increased resistance to amebic cytotoxicity, including CASP3 (600636) activation. The resistance depended on activation of STAT3, but not SHP2 (PTPN11; 176876) or STAT5. The gln223-to-arg (Q223R; 601007.0001) polymorphism in LPR increased susceptibility to amebic cytotoxicity and decreased leptin-dependent STAT3 activation. The authors found that apoptotic genes, including TRIB1 (609461) and SOCS3 (604176), which have opposing roles in apoptosis regulation, were highly enriched in a subset of genes uniquely regulated by STAT3 in response to leptin. Marie et al. (2012) concluded that the LPR-STAT3 signaling pathway restricts amebic pathogenesis and reveals a link between nutrition and susceptibility to infection.

By combining whole-mount confocal immunofluorescence imaging techniques and computational modeling to analyze significant 3-dimensional associations in the mouse bone marrow among vascular structures, stromal cells, and hematopoietic stem cells (HSCs), Kunisaki et al. (2013) showed that quiescent HSCs associate specifically with small arterioles that are preferentially found in endosteal bone marrow. These arterioles are ensheathed exclusively by rare NG2 (CSPG4; 601172)-positive pericytes, distinct from sinusoid-associated LEPR-positive cells. Pharmacologic or genetic activation of the hematopoietic stem cell cycle alters the distribution of HSCs from NG2-positive periarteriolar niches to LEPR-positive perisinusoidal niches. Conditional depletion of NG2-positive cells induces HSC cycling and reduces functional long-term repopulating HSCs in the bone marrow. Kunisaki et al. (2013) concluded that arteriolar niches are indispensable for maintaining HSC quiescence.


Molecular Genetics

Leptin Receptor Deficiency

Clement et al. (1998) reported a mutation in the human leptin receptor gene (601007.0002), a G-to-A transition at the +1 position of intron 16, that causes obesity and pituitary dysfunction (LEPRD; 614963). The mutation was discovered in homozygosity in a consanguineous family of Kabylian (Berber of northern Algeria) origin in which 3 of 9 sibs had morbid obesity with onset in early childhood. In addition to obesity, the homozygous sibs had no pubertal development and reduced secretion of growth hormone (139250) and thyrotropin (see 188540). Clement et al. (1998) considered their results to indicate that leptin is an important physiologic regulator of several endocrine functions in humans.

To determine the prevalence of pathogenic LEPR mutations in severely obese patients, Farooqi et al. (2007) sequenced LEPR in 300 patients with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families. Eight (3%) of the 300 patients had nonsense or missense LEPR mutations, including 7 homozygotes and 1 compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected individuals were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these patients. Their clinical features were less severe than those of patients with congenital leptin deficiency.

In a consanguineous Iranian family in which 9 members had severe early-onset obesity mapping to chromosome 1p31.3, Dehghani et al. (2018) sequenced the LEPR gene and identified homozygosity for a nonsense mutation (Y155X; 601007.0006). The mutation segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, gnomAD, GME Variome Project, or Iranome databases.

LEPR Polymorphism and Relation to Obesity-Related Phenotypes

Gotoda et al. (1997) determined the entire coding sequence of the human leptin receptor cDNA from peripheral blood lymphocytes of 22 morbidly obese patients with body-mass index (BMI) between 35.1 and 60.9 kg/m(2). They identified 5 common DNA sequence variants distributed throughout the coding sequence at codons 109, 223, 343, 656, and 1019, 1 rare silent mutation at codon 986, and 1 novel alternatively spliced form of transcript. None of the 5 common variants, including the 3 that predict amino acid changes, were null mutations causing morbid obesity, because homozygotes for the variant sequences were also found in lean subjects. Furthermore, the frequency of each variant allele and the distribution of genotypes and haplotypes were similar in 190 obese and 132 lean white British males selected from a population-based epidemiologic survey. Gotoda et al. (1997) suggested that mutations in the leptin receptor gene are not a common cause of human obesity.

Rosmond et al. (2000) studied the possible role of the leptin receptor on regulation of blood pressure. Two hundred eighty-four 51-year-old men were selected, and anthropometric, endocrine, metabolic, and hemodynamic variables were examined in relation to LEPR polymorphisms by RFLP analysis. Three polymorphisms were examined: lys109 to arg in exon 4, gln223 to arg in exon 6 (601007.0001), and lys656 to asn in exon 14. In comparison with lys109 homozygotes, arg109 homozygotes (9%) showed lower BMI and abdominal sagittal diameter, as well as lower systolic and diastolic blood pressure. Additionally, arg223 homozygotes (26.8%) showed lower blood pressure than gln223 homozygotes. These lower blood pressure levels were independent of other variables. No differences were found with the lys656-to-asn polymorphism. Measurements of body fat mass correlated with leptin concentration in lys109 homozygotes and in lys109 heterozygotes, but not in arg109 homozygotes. Blood pressure correlated with leptin only in men carrying the wildtype allele lys109. The authors concluded that leptin is associated with blood pressure regulation in men through the leptin receptor. When BMI and leptin are elevated, increased blood pressure is found only with the most prevalent LEPR genotype at codons 109 and 223, whereas variants of this receptor seem to protect from hypertension.

Yiannakouris et al. (2001) evaluated a genetically homogeneous Greek population for associations between body composition variables and 3 common LEPR gene polymorphisms (K109R, Q223R (601007.0001), and K656N) that have potential functional significance and assessed the contributions of these polymorphisms to the variability of obesity. For the Q223R polymorphism, there was a higher prevalence of the R223 allele in the homozygous form among overweight-obese subjects versus normal weight subjects (20.7% vs 4.5%; P = 0.01). Furthermore, simple and multiple regression analyses revealed that the R223 allele in the homozygous form is a significant predictor of both BMI (P = 0.015) and percent fat mass (P = 0.02) even after adjusting for age and gender and explains 4.5% of the variance in percent fat mass and 5% of the variance in BMI. There was no significant difference in allele frequencies or genotype distributions for the K109R or K656N polymorphisms. These findings support the hypothesis that the Q223R polymorphism, but not the K109R or K656N polymorphism, of LEPR is associated with obesity and predicts a small percentage of body weight and body composition variability in a genetically homogeneous population.

Wauters et al. (2001) investigated the relationship between LEPR polymorphisms and glucose and insulin (176730) response to an oral glucose tolerance test (OGTT). Three LEPR polymorphisms (K109R, 601007.0004; Q223R, 601007.0001; and K656N, 601007.0005;) were typed on genomic DNA of 358 overweight and obese women, aged 18 to 60 years. Based on an OGTT, 269 subjects were defined with normal glucose tolerance, and 89 with impaired glucose tolerance. In 24 postmenopausal women with impaired glucose tolerance, associations were found with K109R and K656N for fasting insulin (P = 0.05) and with K109R and Q223R for the insulin response to an OGTT (P less than 0.02). In the same group, trends were found with K656N for fasting glucose as well as in response to the OGTT. In 65 premenopausal women with impaired glucose tolerance, associations were found with K109R and K656N for overall glucose response to the glucose load. In contrast, no associations with insulin or glucose were found in women with normal glucose tolerance. The authors concluded that LEPR polymorphisms are associated with insulin and glucose metabolism in women with impaired glucose homeostasis.

Park et al. (2006) genotyped 11 polymorphisms of the LEPR gene in 775 unrelated Korean patients with type II diabetes and 688 controls. No significant associations between the polymorphisms and the risk of type II diabetes were detected, but the K109R SNP, which they called R109K, showed marginal association with BMI (p = 0.02) and gene dose-dependent effects were observed.

Sun et al. (2010) conducted a genomewide association study of plasma soluble leptin receptor (sOB-R) levels in 1,504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single-nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels, all mapping to LEPR. Analysis of imputed genotypes on autosomal chromosomes revealed an additional 106 SNPs in and adjacent to this gene that reached genomewide significance level. Of these 132 SNPs (including 2 nonsynonymous SNPs, rs1137100 and rs1137101), rs2767485, rs1751492 and rs4655555 remained associated with sOB-R levels at the 0.05 level after adjustment for other univariately associated SNPs in a forward selection procedure. Significant associations with these SNPs were replicated in an independent sample of 875 young males residing in Cyprus.


Animal Model

Takaya et al. (1996) identified a mutation in Obr in Zucker fatty (fa/fa) rats, a missense mutation (an A-to-C conversion at nucleotide position 806) in the extracellular domain of all the isoforms that results in a single amino acid change from gln to pro at position 269. Chua et al. (1996) showed by genetic mapping and genomic analysis that mutations in the mouse and rat leptin receptors account for the mouse diabetes (db) and rat fatty (fa) phenotypes, respectively. Lee et al. (1996) likewise found that mutation in the leptin receptor gene results in db mice. They showed that the murine receptor has at least 6 alternatively spliced forms, 1 of which is expressed at a high level in the hypothalamus and is spliced abnormally in db/db mice. From their studies, Lee et al. (1996) also concluded that abnormal splicing of the Obr mRNA resulted in a mutant protein lacking the cytoplasmic region. Chen et al. (1996) identified an alternatively spliced transcript that encodes a form of mouse Obr with a long intracellular domain. They found that db/db mice also produced this alternatively spliced transcript, but with a 106-bp insertion that prematurely terminates the intracellular domain. They identified a G-to-T transversion in the genomic Obr sequence in these mice. This mutation generates a donor splice site that converts the 106-bp region to a novel exon retained in the Obr transcript. They predicted that the long intracellular domain form of the receptor is crucial for initiating intracellular signal transduction, and as a corollary, the inability to produce this form of Obr leads to the severe obesity phenotype found in db/db mice.

The obese spontaneously hypertensive Koletsky rat strain develop obesity, hyperlipidemia, hyperinsulinemia, and proteinuria with kidney disease, which were thought to be due to a single recessive gene. Breeding data from crosses of the Zucker rat and the Koletsky rat suggested that alleles at the same locus may be responsible for the obese phenotype of these strains. This was proved to be the case by Takaya et al. (1996) who found a nonsense mutation in the leptin receptor gene in the Koletsky rat. Thus the fa/fa (Zucker) rat and the Koletsky rat both have mutations in the leptin receptor, as does the db/db mouse.

Ducy et al. (2000) studied ob/ob and db/db mice, which were obese and hypogonadic. Both mutant mice had increased bone formation, leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype was dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There was no leptin signaling in osteoblasts, but intracerebroventricular infusion of leptin caused bone loss in leptin-deficient and wildtype mice. This study identified leptin as a potent inhibitor of bone formation acting through the central nervous system.

Cohen et al. (2001) generated mice with neuron- and hepatocyte-specific conditional deletion of Lepr. Neuron-specific Lepr-null mice with the lowest levels of hypothalamic Lepr exhibited an obese phenotype, and these obese null mice had elevated plasma levels of leptin, glucose, insulin, and corticosterone, as well as increased hypothalamic agouti-related protein (AGRP; 602311) and neuropeptide Y (NPY; 162640) RNA. Hepatocyte-specific Lepr-null mice weighed the same as controls and had no alterations in body composition. In addition, db/db mice and neuron-specific Lepr-null mice had enlarged fatty livers, whereas the hepatocyte-specific Lepr-null mice did not. Cohen et al. (2001) suggested that the brain is a direct target for the weight-reducing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain.

Balthasar et al. (2004) generated mice with conditional deletion of leptin receptors on proopiomelanocortin (POMC; 176830) neurons and observed mild obesity, hyperleptinemia, and altered expression of hypothalamic neuropeptides. Because the body weight increase was only 18% of that seen in mice with complete deficiency of leptin receptors, the authors concluded that leptin receptors on POMC neurons are required but not solely responsible for leptin's regulation of body weight homeostasis.

Tian et al. (2002) found that the percentage and total number of natural killer (NK) cells in lymphoid organs and peripheral blood were reduced in Lepr-deficient mice. Furthermore, NK cell activation and target cell lysis were retarded in these mice.

Tyr1138 of the leptin receptor long form (LRb) mediates activation of the transcription factor STAT3 (102582) during leptin action. To investigate the contribution of STAT3 signaling to leptin action in vivo, Bates et al. (2003) replaced the gene encoding the leptin receptor (Lepr) in mice with an allele coding for replacement of tyr1138 in LRb with a serine residue that specifically disrupts the LRb-STAT3 signal. Like db/db mice, Lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short, and diabetic, s/s mice are fertile, long, and less hyperglycemic. Furthermore, hypothalamic expression of Npy is elevated in db/db mice but not in s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. Bates et al. (2003) concluded that LRb-STAT3 signaling mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth, and glucose homeostasis.

Bjornholm et al. (2007) showed that mice homozygous for a tyr985-to-leu mutation in LRb were neuroendocrinologically normal but that females demonstrated decreased feeding, decreased expression of orexigenic neuropeptides, protection from high-fat-diet-induced obesity, and increased leptin sensitivity in a sex-biased manner. The authors concluded that leptin activates autoinhibitory signals via LRb tyr985 to attenuate the antiadiposity effects of leptin, especially in females, which may contribute to leptin insensitivity in obesity.

Kaneto et al. (2004) developed a cell-permeable JNK1 (601158) inhibitory peptide. Intraperitoneal administration of the peptide led to its transduction in various tissues in vivo, and this treatment markedly improved insulin resistance and ameliorated glucose tolerance in db/db diabetic mice. Kaneto et al. (2004) concluded that the JNK pathway is critically involved in diabetes and that the cell-permeable JNK inhibitory peptide may have promise as a therapeutic agent for diabetes.

Zhang et al. (2004) selectively deleted tyrosine phosphatase Shp2 (176876) in postmitotic forebrain neurons of mice and observed the development of early-onset obesity with increased serum levels of leptin, insulin, glucose, and triglycerides, although the mutant mice were not hyperphagic. In wildtype mice, the authors found that Shp2 downregulation of Jak2 (147796)/Stat3 activation by leptin (164160) in the hypothalamus was offset by a dominant Shp2 promotion of the leptin-stimulated Erk (see 601795) pathway; thus, Shp2 deletion in the brain results in induction rather than suppression of leptin resistance. Zhang et al. (2004) suggested that a primary function of SHP2 in the postmitotic forebrain is to control energy balance and metabolism, and that SHP2 is a critical signaling component of the leptin receptor in the hypothalamus.

In Koletsky fa(k)/fa(k) (LEPR-null) rats, Morton et al. (2005) observed markedly increased meal size and reduced satiety in response to cholecystokinin (CCK; 118440), suggesting a role for leptin signaling in the response to endogenous signals that promote meal termination. Restoration of LEPR in the area of the hypothalamic arcuate nucleus of fa(k)/fa(k) rats by adenoviral gene therapy normalized the effect of CCK on the activation of neurons in key hindbrain areas for processing satiety signals and also reduced meal size and enhanced CCK-induced satiety. Morton et al. (2005) concluded that forebrain signaling by leptin limits food intake on a meal-to-meal basis by regulating the hindbrain response to short-acting satiety signals.

In mouse models of type II diabetes, either Irs2 -/- (600797) or Lepr -/- (db/db), Uchida et al. (2005) observed progressive accumulation of p27 (CDKN1B; 600778) in the nucleus of pancreatic beta cells. Deletion of Cdkn1b ameliorated hyperglycemia by increasing islet mass and maintaining compensatory hyperinsulinemia, which the authors attributed predominantly to stimulation of pancreatic beta-cell proliferation. Uchida et al. (2005) concluded that p27 contributes to beta-cell failure in the development of type II diabetes in Irs2 -/- and db/db mice.

De Luca et al. (2005) generated db/db mice that were compound hemizygotes for both of the neuron-specific transgenes, synapsin (313440)-Lepr-B and Eno2 (131360)-Lepr-B, and observed complete correction of the obesity and related phenotypes: body composition, insulin sensitivity, cold tolerance, expression of 3 neuropeptide genes (Agrp, Npy, and Pomc), and fertility were fully normalized in the dual transgenic db/db mice. De Luca et al. (2005) concluded that brain-specific signaling is sufficient to reverse the obesity, diabetes, and fertility of db/db mice.

Using in situ peroxidase and immunofluorescence staining in mouse hearts, Raju et al. (2006) localized Cntf receptors (CNTFR; 118946) to the sarcolemma and confirmed the localization by immunoblot on isolated myocytes. Subcutaneous administration of recombinant CNTF (118945) in ob/ob and db/db mice resulted in significant reductions in cardiac hypertrophy. Western blotting showed that both leptin and CNTF activated STAT3 and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) pathways in cultured adult mouse cardiomyocytes and cardiac tissue from ob/ob and db/db mice. Raju et al. (2006) concluded that CNTF plays a role in a cardiac signal transduction pathway that regulates obesity-related left ventricular hypertrophy.

Morioka et al. (2007) generated pancreas-specific Lepr -/- mice and observed improved glucose tolerance due to enhanced early-phase insulin secretion and a greater beta-cell mass secondary to increased beta-cell size and enhanced expression and phosphorylation of p70S6K (RPS6KB1; 608938). Challenging the knockout mice with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Morioka et al. (2007) concluded that leptin plays a critical signaling role in islet biology and suggested that altered leptin action in islets is a factor that contributes to obesity-associated diabetes.

Czupryn et al. (2011) generated physically chimeric hypothalami by microtransplanting small numbers of embryonic enhanced green fluorescent protein-expressing leptin-responsive hypothalamic cells into hypothalami of postnatal Lepr-deficient (db/db) mice, which develop morbid obesity. Donor neurons differentiated and integrated as 4 distinct hypothalamic neuron subtypes, formed functional excitatory and inhibitory synapses, partially restored leptin responsiveness, and ameliorated hyperglycemia and obesity in db/db mice. Czupryn et al. (2011) concluded that their experiments served as a proof of concept that transplanted neurons can functionally reconstitute complex neuronal circuitry in the mammalian brain.


ALLELIC VARIANTS 6 Selected Examples):

.0001   LEPTIN RECEPTOR POLYMORPHISM

LEPR, GLN223ARG
SNP: rs1137101, gnomAD: rs1137101, ClinVar: RCV000009047, RCV000281795, RCV000348520, RCV000518727, RCV001668124

In hypothalamic tissue from lean and obese humans obtained shortly after autopsy in the Washington, D.C. Medical Examiner's Office, Considine et al. (1996) detected an A-to-G sequence polymorphism at nucleotide 668 of the leptin receptor cDNA. This base substitution changed a glutamine to an arginine at position 23 of the leptin receptor protein. Of 15 subjects analyzed, 11 were heterozygous for this base change and 3 were homozygous. There was no difference in the amount of leptin-receptor mRNA in 7 lean and 8 obese subjects as determined by RT-PCR. The occurrence of the polymorphic allele(s) did not correlate with the body mass index in the patients studied. The results suggested that leptin resistance observed in obese humans is not due to a defect in the leptin receptor.

An A/G single-nucleotide polymorphism in the LEPR gene is associated with a gln223-to-arg (Q223R) amino acid polymorphism. Thompson et al. (1997) found that homozygosity for the G allele is associated with lower plasma leptin levels after correction for obesity, gender, and family. Quinton et al. (2001) sought to determine whether similar associations could be observed in Caucasians by studying a community-based population of postmenopausal women in the Sheffield area of the U.K. They found that genotypes at that locus are associated with differences in body mass index, fat mass, and serum leptin levels. Measurement of serum leptin-binding activity indicated that this may reflect changed receptor function associated with genotype.

In a group of postmenopausal women with impaired glucose tolerance, Wauters et al. (2001) found an association of the Q223R polymorphism with insulin response to an oral glucose tolerance test.

Richert et al. (2007) investigated the association of the Q223R polymorphism in the LEPR gene with bone mineral content and areal bone mineral density in prepubertal boys. LEPR genotypes were significantly associated with baseline bone mineral content at the hip (p = 0.017), femur diaphysis (p = 0.019), and radius (p = 0.007), and with height (p = 0.041) as well as with physical activity (p = 0.016). On average, bone mineral content was 8 to 12% lower in arg/arg than in gln/gln carriers, with gln/arg carriers having intermediate values. Associations with height and bone mineral content at femur diaphysis and radius remained significant after 2 years. Significant differences in 2-year bone mass gain at the spine and femur neck were also found among LEPR genotypes. Richert et al. (2007) concluded that the LEPR Q223R polymorphism was associated with bone mass in growing boys. The association, however, was markedly dependent on bone area, body size, and physical activity, in addition to VDR genetic variation, suggesting that the leptin system may modulate bone mass in humans mostly through indirect mechanisms.

Amebiasis, a potentially fatal enteric infection caused by the parasite Entamoeba histolytica, is exacerbated by malnutrition. Duggal et al. (2011) prospectively observed a cohort of Bangladeshi children for 9 years beginning at preschool age for E. histolytica infection and evaluated them for LEPR variants. They found that children carrying the 223R allele of the Q223R polymorphism had 4-fold increased susceptibility to intestinal infection compared with those homozygous for 223Q. Examination of an independent cohort of adult patients showed that those carrying the 223R allele had increased risk of amebic liver abscess. Mice with at least 1 copy of the R allele were more susceptible to amebic infection and exhibited greater levels of mucosal destruction, as well as intestinal epithelial apoptosis, after infection. Duggal et al. (2011) proposed that leptin signaling is important in mucosal defense against amebiasis and that LPR polymorphisms explain differences in susceptibility of children to amebiasis.

Using human cells, Marie et al. (2012) showed that the Q223R polymorphism in LPR increased susceptibility to amebic cytotoxicity and decreased leptin-dependent STAT3 (102582) activation.


.0002   LEPTIN RECEPTOR DEFICIENCY

LEPR, IVS16DS, G-A, +1
SNP: rs1474810899, gnomAD: rs1474810899, ClinVar: RCV000009048

In a consanguineous family of Kabylian (Berber of northern Algeria) origin in which 3 of 9 sibs had morbid obesity with onset in early childhood (LEPRD; 614963), Clement et al. (1998) detected homozygosity for a G-to-A transition at the +1 position of intron 16 of the LEPR gene, causing obesity and pituitary dysfunction. The splice site mutation results in skipping of exon 16, which leads to a truncated protein of 831 amino acids lacking both the transmembrane and intracellular domains.


.0003   REMOVED FROM DATABASE


.0004   LEPTIN RECEPTOR POLYMORPHISM

LEPR, LYS109ARG
SNP: rs1137100, gnomAD: rs1137100, ClinVar: RCV000009049, RCV000309499, RCV000366432, RCV000517666, RCV001707508

In a study of the relationship between LEPR polymorphisms and glucose and insulin response to an oral glucose tolerance test, Wauters et al. (2001) found an association in postmenopausal women with impaired glucose tolerance of the lys109-to-arg (K109R) polymorphism in exon 3 of the LEPR gene with fasting insulin, and of K109R with the insulin response to an oral glucose tolerance test. In premenopausal women with impaired glucose tolerance, they found an association of K109R with overall glucose response to the glucose load.


.0005   LEPTIN RECEPTOR POLYMORPHISM

LEPR, LYS656ASN
SNP: rs1805094, gnomAD: rs1805094, ClinVar: RCV000009050, RCV000266874, RCV000321944, RCV000712216, RCV000730960

In a study of the relationship between LEPR polymorphisms and glucose and insulin response to an oral glucose tolerance test, Wauters et al. (2001) found an association in postmenopausal women with impaired glucose tolerance of the lys656-to-asn (K656N) polymorphism with fasting insulin. In the same group, they found a trend with K656N for fasting glucose as well as in response to the oral glucose tolerance test. In premenopausal women with impaired glucose tolerance, they found an association of K656N with overall glucose response to the glucose load.


.0006   LEPTIN RECEPTOR DEFICIENCY

LEPR, TYR155TER
SNP: rs1557670950, ClinVar: RCV000760143

In a consanguineous Iranian family in which 9 members had severe early-onset obesity (LEPRD; 614963) mapping to chromosome 1p31.3, Dehghani et al. (2018) sequenced the LEPR gene and identified homozygosity for a c.464T-G transversion (c.464T-G, NM_002303.5) in exon 3, resulting in a tyr155-to-ter (Y155X) substitution. The mutation affects the extracellular N terminus, thus impacting all transcripts, and is predicted to result in a complete loss of function due to nonsense-mediated decay. The mutation segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, gnomAD, GME Variome Project, or Iranome databases.


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Contributors:
Sonja A. Rasmussen - updated : 03/12/2019
Paul J. Converse - updated : 03/07/2016
Ada Hamosh - updated : 2/5/2014
Ada Hamosh - updated : 2/8/2012
Ada Hamosh - updated : 1/9/2012
George E. Tiller - updated : 12/1/2011
George E. Tiller - updated : 10/20/2009
Marla J. F. O'Neill - updated : 12/19/2008
John A. Phillips, III - updated : 6/24/2008
Marla J. F. O'Neill - updated : 11/5/2007
Marla J. F. O'Neill - updated : 10/24/2007
Victor A. McKusick - updated : 2/5/2007
Marla J. F. O'Neill - updated : 4/12/2006
Marla J. F. O'Neill - updated : 4/6/2006
Marla J. F. O'Neill - updated : 1/5/2006
Marla J. F. O'Neill - updated : 7/8/2005
Marla J. F. O'Neill - updated : 4/25/2005
Marla J. F. O'Neill - updated : 4/11/2005
Marla J. F. O'Neill - updated : 3/23/2005
Ada Hamosh - updated : 11/22/2004
Marla J. F. O'Neill - updated : 11/18/2004
Paul J. Converse - updated : 1/8/2004
Ada Hamosh - updated : 2/21/2003
John A. Phillips, III - updated : 3/5/2002
John A. Phillips, III - updated : 2/14/2002
John A. Phillips, III - updated : 10/1/2001
Victor A. McKusick - updated : 4/6/2001
Stylianos E. Antonarakis - updated : 2/8/2000
Victor A. McKusick - updated : 9/11/1998
Ada Hamosh - updated : 4/6/1998
Victor A. McKusick - updated : 8/25/1997
Victor A. McKusick - updated : 6/23/1997
Victor A. McKusick - updated : 3/4/1997
Victor A. McKusick - updated : 2/6/1997
Lori M. Kelman - updated : 12/6/1996
Alan F. Scott - updated : 2/15/1996

Creation Date:
Victor A. McKusick : 1/23/1996

Edit History:
carol : 05/01/2019
carol : 03/12/2019
carol : 09/15/2016
mgross : 03/07/2016
alopez : 11/10/2015
alopez : 2/5/2014
alopez : 2/5/2014
carol : 4/3/2013
alopez : 12/10/2012
alopez : 2/10/2012
terry : 2/8/2012
alopez : 1/9/2012
alopez : 12/6/2011
terry : 12/1/2011
alopez : 9/23/2010
mgross : 10/20/2009
wwang : 12/30/2008
terry : 12/19/2008
alopez : 6/24/2008
wwang : 11/14/2007
terry : 11/5/2007
wwang : 10/25/2007
terry : 10/24/2007
wwang : 2/7/2007
terry : 2/5/2007
alopez : 2/1/2007
wwang : 4/17/2006
terry : 4/12/2006
wwang : 4/7/2006
terry : 4/6/2006
wwang : 1/11/2006
terry : 1/5/2006
wwang : 7/20/2005
wwang : 7/15/2005
terry : 7/8/2005
wwang : 4/29/2005
wwang : 4/27/2005
terry : 4/25/2005
tkritzer : 4/13/2005
terry : 4/11/2005
terry : 4/5/2005
tkritzer : 3/23/2005
alopez : 12/2/2004
terry : 11/22/2004
tkritzer : 11/18/2004
mgross : 1/8/2004
cwells : 11/10/2003
joanna : 7/24/2003
alopez : 2/25/2003
terry : 2/21/2003
alopez : 3/5/2002
alopez : 2/14/2002
carol : 11/27/2001
alopez : 10/1/2001
cwells : 5/2/2001
mcapotos : 4/9/2001
terry : 4/6/2001
mgross : 2/8/2000
alopez : 9/13/1998
terry : 9/11/1998
terry : 9/11/1998
dkim : 9/10/1998
joanna : 5/15/1998
alopez : 4/6/1998
mark : 8/25/1997
alopez : 7/30/1997
mark : 7/8/1997
jenny : 6/23/1997
terry : 6/19/1997
jenny : 3/4/1997
terry : 2/24/1997
terry : 2/6/1997
terry : 1/24/1997
jamie : 1/21/1997
mark : 12/21/1996
terry : 12/16/1996
jamie : 12/6/1996
jenny : 12/6/1996
mark : 11/20/1996
terry : 11/14/1996
mark : 11/12/1996
terry : 11/4/1996
mark : 9/30/1996
terry : 9/26/1996
mark : 9/11/1996
terry : 9/11/1996
terry : 9/10/1996
terry : 9/9/1996
terry : 9/9/1996
terry : 9/3/1996
mark : 5/28/1996
terry : 4/17/1996
mark : 3/9/1996
terry : 3/4/1996
terry : 3/4/1996
mark : 2/15/1996
terry : 2/6/1996
mark : 1/23/1996