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Berardinelli-Seip Congenital Lipodystrophy

Synonyms: Berardinelli-Seip Congenital Generalized Lipodystrophy, Congenital Generalized Lipodystrophy
, MD, PhD
Centre de Génétique Humaine
Université de Franche-Comté
Besançon, France

Initial Posting: ; Last Update: June 28, 2012.


Clinical characteristics.

Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.


The diagnosis of BSCL is established by clinical findings including lipoatrophy affecting the trunk, limbs, and face; acromegaloid features; hepatomegaly; elevated serum concentration of triglycerides; and insulin resistance. AGPAT2 and BSCL2 are the genes in which mutations are known to cause Berardinelli-Seip congenital generalized lipodystrophy type 1 and type 2 respectively.


Treatment of manifestations: Restriction of total fat intake between 20% and 30% of total dietary energy maintains normal triglyceride serum concentration. Diabetes mellitus is managed as in childhood-onset diabetes mellitus.

Surveillance: Regular screening for glycosuria as a manifestation of diabetes mellitus, which usually starts in the teens (average age 12 years) but has also been described in infancy; monitoring for potential retinal, peripheral nerve, and renal complications of diabetes mellitus; yearly echocardiogram; yearly liver ultrasound examination to detect fatty infiltration.

Genetic counseling.

BSCL is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.


Clinical Diagnosis

Three major criteria or two major criteria plus two or more minor criteria make a diagnosis of BSCL very likely.

Major criteria

  • Lipoatrophy affecting the trunk, limbs, and face. Generalized lipodystrophy is apparent at birth. In some individuals, the face may be normal at birth with lipoatrophy becoming apparent during the first months of life. Lipoatrophy gives an athletic appearance, especially because skeletal muscle hypertrophy is also present.
  • Acromegaloid features include gigantism, muscular hypertrophy, advanced bone age, prognathism, prominent orbital ridges, enlarged hands and feet, clitoromegaly, and enlarged external genitalia in the male.
  • Hepatomegaly. Liver enlargement is secondary to fatty liver early on and to cirrhosis late in the disease course.
  • Elevated serum concentration of triglycerides. Serum concentration of triglycerides can be elevated up to 80 g/L, and is sometimes associated with hypercholesterolemia.
  • Insulin resistance. Elevated serum concentrations of insulin and C-peptide may occur starting in the first years of life. Overt clinical diabetes mellitus usually develops during the second decade. Its early clinical expression is acanthosis nigricans of the groin, neck, and axillae, which may have, in some cases, a verrucous appearance.

Minor criteria

  • Hypertrophic cardiomyopathy may be present in infancy or develop later in life.
  • Psychomotor retardation or mild (IQ 50-70) to moderate (IQ 35-50) intellectual impairment. Approximately 80% of individuals with mutations in BSCL2 have mild-to-moderate intellectual impairment, whereas only 10% of individuals with mutations in AGPAT2 have intellectual impairment.
  • Hirsutism manifests with low frontal and posterior hairline; hypertrichosis is apparently independent of hormonal stimulation.
  • Precocious puberty in females. In a series of 75 individuals with BSCL, three females underwent puberty before age seven years [Van Maldergem et al 2002].
  • Bone cysts occur in 8%-20% of affected individuals and have a polycystic appearance on x-ray. Located in the epiphyseal and metaphyseal regions of the long bones, bone cysts are often diagnosed during the second decade and are mostly observed in individuals with mutations in AGPAT2.
  • Phlebomegaly. Prominence of the veins of the lower and upper limbs is observed, in part because of the lack of subcutaneous fat.

Molecular Genetic Testing

Genes. AGPAT2 and BSCL2, the two genes in which mutations are known to cause Berardinelli-Seip congenital lipodystrophy, are thought to account for 95% of cases of congenital generalized lipodystrophy [Boutet et al 2009]:

  • AGPAT2, associated with BSCL type 1
  • BSCL2, associated with BSCL type 2

Evidence for locus heterogeneity. Magré et al [2003] found that 92/94 affected individuals harbor mutations that are either in BSCL2 or AGPAT2 or appear to be linked to their loci; Agarwal et al [2004] found this to be the case in 44/47 affected persons. Recent reports provide evidence for at least two additional loci associated with congenital generalized lipodystrophy and other findings, CGL3 and CGL4, resulting from mutations in CAV1 and PTRF respectively (see Differential Diagnosis) [Kim et al 2008, Simha et al 2008, Hayashi et al 2009].

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Berardinelli-Seip Congenital Lipodystrophy

Proportion of All BSCLGene 1Test MethodMutations Detected 2
See footnote 3BSCL2Sequence analysis 4Sequence variants 5
Deletion / duplication analysis 6Exonic or whole-gene deletions
See footnote 7AGPAT2Sequence analysis 4Sequence variants

2. See Molecular Genetics for information on allelic variants.

3. The proportion of BSCL caused by mutations in each of the two genes is closely related to the population under study:

BSCL2 disease-causing mutations account for the majority of cases in the Berardinelli-Seip study group [Van Maldergem et al 2002, Magré et al 2003] in which affected individuals originated mostly from Europe, the Middle East, and sub-Saharan Africa; studies from Brazil draw similar conclusions (18/26) [Fu et al 2004, Miranda et al 2009]; likewise, in a small sample from Japan, three of four affected individuals were homozygous for a BSCL2 mutation [Ebihara et al 2004].

AGPAT2 disease-causing mutations accounted for the majority of affected individuals (26/45) in a study from the US [Agarwal et al 2003]. Of note, many individuals in this cohort are of African ancestry.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. BSCL2 frameshift mutation c.315_319delGTATC is identified in the Lebanese population [Magré et al 2001]. Other mutations are identified in individuals of European, Middle Eastern, Asian, or Portuguese ancestry.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Nearly all individuals of African origin with BSCL type 1 have the AGPAT2 c.493-2A>G mutation. Other mutations have now been described worldwide in diverse populations.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis is established by clinical findings and confirmed with molecular genetic testing.

  • In individuals with intellectual disability or cardiomyopathy, sequencing of BSCL2 should be considered first.
  • The order of molecular genetic testing may also be stratified by the ethnicity of the affected individual (see Table 1, footnotes 3 and 7).

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Characteristics

Clinical Description

Berardinelli-Seip congenital lipodystrophy (BSCL) is mostly diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Hepatomegaly secondary to hepatic steatosis occurs in virtually all individuals with BSCL. Skeletal muscle hypertrophy occurs in all affected individuals.

Affected individuals develop insulin resistance and approximately 25%-35% of individuals develop diabetes mellitus between ages 15 and 20 years. Diabetes mellitus can be difficult to control.

Hypertrophic cardiomyopathy is reported in 20%-25% of individuals and is a significant cause of morbidity from cardiac failure and early mortality around age 30 years. Affected individuals have died as early as age 19 months of complications of cardiomyopathy.

Intellectual impairment is common, especially in individuals with mutations in BSCL2. Intrafamilial variability, including variability in intellectual impairment, exists.

Neonatal or infantile presentation. Severe forms of BSCL may have prenatal onset with intrauterine growth retardation. Presentation in the first months of life includes failure to thrive (or conversely gigantism), hepatomegaly, lipoatrophy, facial dysmorphia, enlarged tongue, or developmental delay. All children with the neonatal or infantile presentation demonstrate lipoatrophy in the first year of life.

Recently, two children (one of Chinese and the other of Turkish ancestry) came to medical attention in the first year of life with cardiac failure associated with hypertrophic cardiomyopathy [Friguls et al 2009; De Vroede, personal communication]. Homozygous missense mutations were identified in both. Additional reports are required to confirm the existence of a phenotype that presents with cardiac manifestations. A third patient [Debray et al, submitted] confirms the existence of a CGL1 endophenotype comprising early-onset hypertrophic cardiomyopathy.

Juvenile presentation. Diabetes mellitus manifest by weight loss, polydipsia, polyuria, or asthenia is frequently the presenting finding in the second decade.

Adult presentation. BSCL presents on occasion in early adulthood with diabetes mellitus. Individuals may first be seen in the plastic surgery clinic seeking cosmetic improvement of facial lipoatrophy or in the cardiology clinic or gastroenterology clinic for manifestations such as hypertrophic cardiomyopathy or hepatomegaly. Some women present with oligomenorrhea, amenorrhea, or features of polycystic ovary syndrome.

Genotype-Phenotype Correlations

Approximately 80% of individuals with mutations in BSCL2 have mild-to-moderate intellectual impairment, whereas only 10% of individuals with mutations in AGPAT2 have intellectual impairment.

No correlation exists between the site and type of BSCL2 mutation and intellectual impairment [Van Maldergem et al 2002]. Furthermore, related and unrelated individuals with the same mutation may be discordant for intellectual impairment.

Individuals with BSCL2 mutations have increased prevalence of cardiomyopathy.

There appears to be no relationship between the site and type of AGPAT2 mutations and severity of lipodystrophy or metabolic complications.


Berardinelli-Seip syndrome is named after W Berardinelli, who reported the first affected individuals from Brazil in 1954. The syndrome was confirmed in 1959 in Norway by M Seip, whose patients originated from the county of Rogaland. In the European literature, the terms Seip syndrome, generalized lipodystrophy, congenital generalized lipodystrophy, or total lipodystrophy have been used.

Brunzell syndrome (OMIM 272500) is the association of bone cysts and lipoatrophic diabetes mellitus described in five affected African Americans from the same sibship. Originally Brunzell syndrome was thought to be a separate entity, but it is now generally recognized that bone cysts represent a rare complication of Berardinelli-Seip congenital lipodystrophy. Furthermore, Fu et al [2004] identified mutations in AGPAT2 in three sibs with Brunzell syndrome.

After onset of diabetes mellitus, some have termed individuals with BSCL as having "lipoatrophic diabetes."

Lawrence syndrome is synonymous with acquired generalized lipodystrophy [Garg 2011].


More than three hundred cases of BSCL have been reported in the medical literature. Prevalence estimates:

Individuals with mutations in AGPAT2 typically originate from sub-Saharan Africa and the Maghreb (Morocco, Algeria, and Tunisia) and occasionally from Middle Eastern countries (e.g., Turkey) and northern Europe [Van Maldergem et al 2002].

Individuals with mutations in BSCL2 have been described worldwide including a significant proportion of whites of varying ethnicities (Norway, United Kingdom, Portugal and its former colonies, Mediterranean countries) and Middle Eastern Arabs [Van Maldergem et al 2002].

Differential Diagnosis

See Lipodystrophy, Congenital Generalized: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Congenital generalized lipodystrohy 3 (CGL3). Individuals with this condition typically have serum creatine kinase concentrations between 2.5 to ten times the upper limit of normal in addition to features resembling classic BSCL [Kim et al 2008]. Two sibs of Hispanic ancestry with a homozygous CAV1 missense mutation who have hypotonia, elevated serum creatine kinase, atlas-axis instability, and generalized lipodystrophy have been described [Simha et al 2008].

Congenital generalized lipodystrohy 4 (CGL4). Generalized lipodystrophy, distal myopathy, muscular hypertrophy, hypertriglyceridemia, insulin resistance, elevated serum creatine kinase concentration, and normal intelligence were described in five Japanese individuals with mutations in PTRF, encoding polymerase I and transcript release factor of caveloe [Hayashi et al 2009]. A series of affected individuals with cardiac arrhythmia originating from Oman and the UK were reported by Rajab et al [2010]. The PTRF caveolar-associated protein is thought to play an essential role in the formation of caveloe (invaginations of the plasma membrane involved in many cellular processes, including clathrin-independent endocytosis, cholesterol transport, and signal transduction) and the stabilization of caveolins, proteins present in the caveloe. These new data confirm caveolin deficiency as a cause of the lipodystrophic process.

Further diagnoses to consider include the following:

In infancy

In childhood

  • Familial partial Dunnigan-Koëberling lipodystrophy (OMIM 151660)
  • Rabson-Mendenhall syndrome (OMIM 262190)
  • Insulin-dependent diabetes mellitus
  • Acquired generalized lipodystrophy (Lawrence syndrome) [Misra & Garg 2003]. Three subtypes exist.
  • Mandibuloacral dysplasia (MAD) caused by LMNA/C and ZMPSTE24 mutations

In adulthood

  • Acquired partial lipodystrophy (Barraquer-Simons syndrome)
  • Lipodystrophy associated with human immunodeficiency virus infection
  • Partial lipodystrophy with C3 nephritic factor
  • Acquired generalized lipodystrophy (Lawrence syndrome)


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Berardinelli-Seip congenital lipodystrophy (BSCL), the following clinical evaluations are recommended:

  • Assessment of pubertal status according to Tanner's charts
  • Neurologic examination
  • Search for signs of liver and muscle dysfunction
  • Search for evidence of hypertrophic cardiomyopathy
  • Search for evidence of possible orthopedic problems (reduced hip mobility, genu valgum)
  • Complete ophthalmologic examination, including slit lamp examination
  • Testing of cognitive ability with age-appropriate scales

The following additional investigations are recommended:

  • Complete blood count
  • Serum concentration of creatine kinase
  • Serum concentration of electrolytes, insulin, AST, alanine transaminase, urea, creatinine, C-peptide, triglycerides, cholesterol
  • Serum proteins and electrophoresis
  • Oral glucose tolerance test. When appropriate: clamp glucose homeostasis study
  • When appropriate: GH, IgG, A, M, E, C3 nephritic factor, CH50, C3, C4 apolipoproteins, hypothalamo-pituitary dynamic tests
  • Echocardiogram
  • Whole-body MRI to determine possible residual mechanical “brown” adipose tissue, which is present in CGL1, but not CGL2 [Simha & Garg 2003]
  • Liver ultrasound examination
  • Renal ultrasound examination to evaluate for kidney size
  • Skeletal survey, especially long bones; search for bone cysts and evaluation of bone age maturation
  • Dual energy x-ray absorptiometry (DEXA) scan for assessment of bone density to evaluate for osteopenia
  • Medical genetics consultation

Treatment of Manifestations

Restriction of total fat intake between 20% and 30% of total dietary energy is often sufficient to maintain normal triglyceride serum concentration.

Fibric acid derivatives and n-3 polyunsaturated fatty acids derived from fish oils can be tried for the treatment of extreme hypertriglyceridemia.

Leptin treatment has proven successful in controlling both hypertriglyceridemia and diabetes mellitus [Garg et al 1999, Beltrand et al 2007, Ebihara et al 2007], but its availability outside of clinical trials remains limited [Simha et al 2002].

A major industrial pharmaceutical company is developing a commercial form of leptin which may become available as early as 2013. Management of diabetes mellitus does not differ from that of childhood-onset diabetes mellitus.

Special education is required for individuals with psychomotor retardation or intellectual disability.

Prevention of Primary Manifestations

Dietary restriction of total fat intake may prevent hypertriglyceridemia (see Treatment of Manifestations).


The following are appropriate:

  • Screening for glycosuria as a manifestation of diabetes mellitus
  • For individuals with diabetes mellitus, follow-up in a diabetes clinic every six months to monitor for possible retinal, peripheral nerve, and renal complications
  • Yearly cardiac ultrasound and EKG
  • Yearly liver ultrasound examination to detect fatty infiltration

Agents/Circumstances to Avoid

Excessive dietary fat intake should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Affected pregnant women should be followed in a high-risk pregnancy care unit by a multidisciplinary team including a specialist in fetal medicine and an expert in diabetic management. Pregnancy may increase the risk of diabetic decompensation. Babies born to women with diabetes are at an increased risk for fetal anomalies and postnatal complications compared to babies born to women without diabetes.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.


Other drugs, including fenfluramine, have no proven efficacy and should be avoided.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Berardinelli-Seip congenital lipodystrophy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic, although increased incidence of diabetes mellitus is suggested.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic, although increased incidence of diabetes mellitus is suggested.

Offspring of a proband. The offspring of an individual with BSCL are obligate heterozygotes (carriers) for a disease-causing mutation:

  • Pregnancies in individuals with BSCL type 1 have been described [Van Maldergem et al 2002].
  • Many individuals with BSCL type 2 (BSCL2) do not reproduce.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

BSCL1. Carrier testing for mutations in AGPAT2 is possible if the disease-causing mutations in the family are known.

BSCL2. Carrier testing for mutations in BSCL2 is possible if the disease-causing mutations in the family are known.

Related Genetic Counseling Issues

Differentiation between BSCL type 1 and BSCL type 2 may be useful for purposes of genetic counseling, particularly if the affected individual is too young for mental development to have been clearly characterized.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for BSCL caused by BSCL2 or AGPAT2 mutations is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • American Diabetes Association (ADA)
    Phone: 1-800-DIABETES (800-342-2383)
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    United Kingdom
    Phone: 0800-652-3181
  • Diabetes UK
    United Kingdom
    Phone: 0345 123 2399
    Fax: 020 7424 1001

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Berardinelli-Seip Congenital Lipodystrophy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Berardinelli-Seip Congenital Lipodystrophy (View All in OMIM)


Molecular Genetic Pathogenesis

While little is known on the precise function of seipin, the role of AGPAT2 (1-acyl-sn-glycerol-3-phosphate acyltransferase beta) as a key enzyme in the biosynthesis of triglycerides is well established. Seipin is predicted to be a membrane protein with two transmembrane domains between residues 31-53 and residues 230-252. Studies using confocal analysis and density subcellular fractionation revealed that seipin is mainly located in endoplasmic reticulum (ER). The proteinase K assay demonstrated that seipin is an ER membrane-resident protein with a luminal loop domain and with both termini facing the cytoplasm [Cartwright & Goodman 2012].

It was initially thought that seipin acted as a transcription factor important for stem cell differentiation. Interspecies comparisons indicate a highly conserved region spanning the first 280 amino acids, based on the first reported length of 398 amino acids. Within this region an N-terminal CSSS sequence, present in virtually all species, has been postulated to be implicated in a putative interaction with another molecule.

Interestingly, the possible leucine zipper domain contained in the first 280 amino acids of the protein, based on motif searches, is very similar to that contained in the sterol element-binding proteins (SREBPs) which are also located in the endoplasmic reticulum (ER) and also have two transmembrane domains. The latter are transcription factors with a role in regulation of cholesterol biosynthesis and uptake. Study of yeast seipin indicates that it is located at the junction of ER and lipid droplets called adiposomes. When seipin is absent, irregularly shaped small lipid droplets replace these well-formed adiposomes.

These findings argue for a direct implication in formation or maintenance of these lipid-containing vesicles. In support of a key role for seipin as an adipogenic transcription factor, it was shown in a knockdown mouse model that synthesis of AGPAT2 and DGAT2 are strongly reduced [Ito & Suzuki 2009]. In keeping with this hypothesis, a series of knockdown experiments conducted in vitro by a British group using small hairpin RNA (shRNA) indicated a failure to induce the lipogenic enzymes AGPAT2 and DGAT2. Interference with some adipogenic transcription factors including peroxisome proliferator-activated receptor (PPAR-gamma) and CAAT/enhancer binding protein-alpha was also observed, as if seipin were located upstream in the metabolic pathway. However, a low expression of seipin in adipose tissue could point to an action through secretory factors [Payne et al 2008]. Moreover, a significant reduction of the expression of major genes involved in triglyceride biosynthesis, namely AGPAT2, lipin 1, and DGAT2, is observed in the knockdown experiments. Lipid accumulation is also inhibited.

Interestingly, both BSCL2 nonsense mutations (frequent) and missense mutations (rare) observed in humans have been modeled by Payne et al [2008]. The p.Ala212Pro mutant protein encoded by a missense mutation, observed in a cluster of affected individuals from Norway initially described by Seip in the late 1950s, has been studied. Based on mRNA quantification, BSCL2 protein western blotting studies, and immunolocalization studies, the authors concluded that the p.Ala212Pro mutant protein resulted in mislocalization of adiposomes at the junction of nuclear membrane and ER, while the p.Arg275Ter mutant protein gave rise to the appearance of the above-described misshapen lipid droplets in their orthotopic ER localization [Payne et al 2008]. This putative adipogenic role of seipin would not give, at first glance, an explanation for the mental impairment often observed in individuals with BSCL.


Gene structure. AGPAT2 consists of six exons spanning less than 20 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Homozygous or compound heterozygous AGPAT2 mutations are associated with BSCL. Agarwal et al [2002] identified various AGPAT2 mutations in 11 pedigrees, including a deletion resulting in a frameshift mutation and premature termination codon, nonsense mutations, splice site mutations, missense mutations, and single amino-acid deletions. Magré et al [2003] also reported various mutations in 38 individuals from 30 pedigrees (for more information, see databases in Table A).

Table 2.

Selected AGPAT2 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
(c.IVS1-2A>G) 2
(c.IVS3-1G>C) 2
(c.del317_588) 2
(c.IVS4-2A>G) 2

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Recurrent mutation

Normal gene product. The AGPAT2 protein, 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (also known as lysophosphatidic acid acyltransferase beta [LPAAT]), has 278 amino acids and belongs to the family of acyltransferases. The AGPAT2 enzyme catalyzes an essential reaction in the biosynthetic pathway of glycerophospholipids and triacylglycerol [Agarwal et al 2002].

Abnormal gene product. Mutations in AGPAT2 may cause congenital lipodystrophy by inhibiting/reducing triacylglycerol synthesis and storage in adipocytes. It is also likely that reduced AGPAT2 activity could increase tissue levels of lysophosphatidic acid, which may negatively affect adipocyte functions [Agarwal et al 2002].


Gene structure. BSCL2 consists of 11 exons spanning at least 14 kb. The putative translation initiation codon is located in the second exon. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Homozygous or compound heterozygous BSCL2 mutations are associated with BSCL. Magré et al [2001] identified several different mutations in BSCL2 among 44 individuals, including microdeletions, small insertions and deletions, and five nucleotide substitutions. The majority of mutations resulted in a frameshift or a premature stop codon (for more information, see databases in Table A).

Table 3.

Selected BSCL2 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
(c.324_325 insA)
c.412C>T 2p.Arg138Ter
(c.IVS6-2 A>C)

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Recurrent mutation

Normal gene product. BSCL2 encodes a 398 amino-acid protein, seipin (isoform 2, NP_116056.3). Seipin has at least two hydrophobic amino acid stretches, indicating that it could be a transmembrane protein. The function of seipin is unknown [Magré et al 2001].

Seipin also occurs as another isoform. BSCL2 also encodes a protein of 462 amino acids (isoform 1, NP_001116427.1) (versus 398 amino acids reported in the seminal paper); the 398-amino acid-based numbering is still used in order to avoid inconsistencies linked to re-numbering.

Seipin is composed of 11 exons and has no significant homology to other known proteins. Multiple seipin transcripts of 1.8, 2.0 and 2.4 kb have been identified by RNA blot analysis. The 1.8- and 2.4-kb transcripts are ubiquitous whereas the 2.0 kb is expressed selectively and at high levels in brain and testis. It has been postulated that this distribution could account for the intellectual disability, voracious appetite, and macrogenitosomia observed in BSCL type 2.

Abnormal gene product. The majority of BSCL2 variants are null mutations that are predicted to result in severe disruption of the protein function.


Literature Cited

  1. Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet. 2002;31:21–3. [PubMed: 11967537]
  2. Agarwal AK, Barnes RI, Garg A. Genetic basis of congenital generalized lipodystrophy. Int J Obes Relat Metab Disord. 2004;28:336–9. [PubMed: 14557833]
  3. Agarwal AK, Garg A. Genetic disorders of adipose tissue development, differentiation, and death. Annu Rev Genomics Hum Genet. 2006;7:175–99. [PubMed: 16722806]
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  5. Beltrand J, Beregszaszi M, Chevenne D, Sebag G, De Kerdanet M, Huet F, Polak M, Tubiana-Rufi N, Lacombe D, De Paoli M, Levy-Marchal C. Metabolic correction induced by leptin replacement treatment in young children with Berardinelli-Seip congenital lipoatrophy. Pediatrics. 2007;120:e291–6. [PubMed: 17671040]
  6. Boutet E, El Mourabit H, Prot M, Nemani M, Khallouf E, Colard O, Maurice M, Durand-Schneider AM, Chretien Y, Gres S, Wolf C, Saulnier-Blache JS, Capeau J, Magré J. Seipin deficiency alters fatty acid delta9 desaturation and lipid droplet formation in Berardinelli-Seip congenital lipodystrophy. Biochimie. 2009;91:796–803. [PubMed: 19278620]
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Suggested Reading

  1. Gomes KB, Pardini VC, Fernandes AP. Clinical and molecular aspects of Berardinelli-Seip congenital lipodystrophy. Clin Chim Acta. 2009;402:1–6. [PubMed: 19167372]

Chapter Notes

Author Notes

Dr. Van Maldergem is a teacher of Human Genetics with 25 years' experience in clinical genetics. He is the coordinator of the Berardinelli-Seip study group (created in 1993) and organizer of the first international conference on lipodystrophies (Brussels, 1997).

Revision History

  • 28 June 2012 (me) Comprehensive update posted live
  • 23 February 2010 (me) Comprehensive update posted live
  • 23 August 2007 (cd) Revision: sequence analysis and prenatal diagnosis for BSCL type 1 available on a clinical basis
  • 21 December 2005 (me) Comprehensive update posted to live Web site
  • 3 August 2004 (lvm) Revision: Genetically Related Disorders
  • 8 September 2003 (me) Review posted to live Web site
  • 24 April 2003 (lvm) Original submission
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