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Donnai-Barrow Syndrome

Synonyms: Faciooculoacousticorenal Syndrome, FOAR Syndrome, DBS/FOAR Syndrome

, PhD, FACMG, , MD, , MD, and , MD, FACMG.

Author Information
, PhD, FACMG
Pathology Department
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, Massachusetts
, MD
Medical Genetics
University of Manchester and
Regional Genetics Service
St Mary's Hospital
Manchester, United Kingdom
, MD
General Surgeon
Department of Surgery
The Medical College of Wisconsin
Milwaukee, Wisconsin
, MD, FACMG
Pediatrician, Mass General Hospital for Children
Geneticist, Department of Surgery, Children's Hospital Boston
Harvard Medical School
Boston, Massachusetts

Initial Posting: ; Last Update: June 28, 2011.

Summary

Disease characteristics. Donnai-Barrow syndrome (DBS) is characterized by typical craniofacial features (ocular hypertelorism, enlarged fontanelle), ocular findings (high myopia, retinal detachment, progressive vision loss, and iris coloboma), sensorineural hearing loss, agenesis of the corpus callosum, intellectual disability, and congenital diaphragmatic hernia (CDH) and/or omphalocele. Both inter- and intrafamilial phenotypic variability are observed.

Diagnosis/testing. The diagnosis of DBS is based on the combination of characteristic clinical features and a distinctive pattern of low-molecular-weight proteinuria. LRP2, encoding the protein low-density lipoprotein receptor-related protein 2 precursor (megalin), is the only gene known to be associated with DBS.

Management. Treatment of manifestations: Surgical repair of omphalocele and/or diaphragmatic hernia; corrective lenses for myopia; retinal detachment preventative treatments (e.g., peripheral laser photocoagulation); hearing aids and/or cochlear implants for hearing loss; education tailored to degree of intellectual, visual, and hearing abilities; antiepileptic drugs for seizures.

Surveillance: Serial audiologic examinations; close ophthalmic surveillance to monitor for retinal detachment; serial renal function serology including blood urea nitrogen (BUN) and creatinine concentrations.

Genetic counseling. DBS is inherited in an autosomal recessive manner. In general, the parents of an affected child are obligate heterozygotes with each carrying one mutant allele; one instance of uniparental disomy has been reported. When both parents are known to be mutation carriers, 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. If the disease-causing mutations in the family are known, carrier testing for at-risk relatives and prenatal testing of pregnancies at increased risk are possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

Clinical Diagnosis

The diagnosis of Donnai-Barrow syndrome (DBS) is based on the recognition of characteristic clinical features combined with a distinctive pattern of low-molecular-weight proteinuria. It is confirmed by detection of mutations in LRP2, which codes for the protein low-density lipoprotein receptor-related protein 2 precursor (megalin).

No single feature is pathognomonic for DBS, nor have diagnostic criteria been formalized. However, the diagnosis should be entertained when several of the following structural and functional anomalies are present:

Craniofacial. Marked ocular hypertelorism, large anterior fontanelle, wide metopic suture, widow’s peak in anterior hairline, depressed nasal bridge, short nose, and posterior rotation of the ears are present in nearly 100% of affected individuals. The facial appearance, although not coarse, is characteristic (see Figure 1).

Figure 1

Figure

Figure 1. Face: same male with Donnai-Barrow syndrome over time

A. At age six months; broad forehead prominent ocular hypertelorism, left iris coloboma, and short nose

B. At age 2.5 years; same features are apparent. (more...)

Ocular. Enlarged globes (leading to the appearance of prominent eyes) and downslanting palpebral fissures are found in all affected individuals. Iris coloboma is observed in a minority of patients. High myopia (>6 diopters), retinal detachment, retinal dystrophy, and progressive visual loss are observed.

Sensorineural hearing loss is a universal finding.

Diaphragmatic hernia (or eventration) and/or omphalocele (or umbilical hernia) are each reported in approximately 50% of affected individuals. The two defects occur together in approximately one third of cases. Note: The absence of either or both does not exclude the diagnosis.

Neurologic. Either complete or partial agenesis of corpus callosum (ACC) is reported in almost all individuals clinically diagnosed with DBS (see Figure 2). Interestingly, ACC was not observed in any individuals with the clinical diagnosis of faciooculoacousticorenal (FOAR) syndrome (including the LRP2 mutation-confirmed case reported by Devriendt et al [1998] with overlapping DBS/FOAR features).

Figure 2

Figure

Figure 2. MRI in a three-year-old female demonstrates numerous abnormalities including hypogenesis of the corpus callosum (most notably involving the rostrum and splenium) (long white arrow), partially empty sella turcica (S), and small pons (P).

Note: FOAR syndrome, or faciooculoacousticorenal syndrome, is now recognized to be allelic to DBS.

Developmental delay is almost always present.

Testing

Absent or abnormally functioning megalin, the protein encoded by LRP2, prevents normal renal proximal tubule reuptake of megalin ligands, resulting in excess spillage of low-molecular-weight proteins in the urine in 100% of individuals with DBS.

Two important low-molecular-weight proteins identified by urinary protein electrophoresis:

  • Retinol-binding protein (RBP)
  • Vitamin D-binding protein (DBP)

Note: Limited data suggest that excess urinary spillage of these moieties may result in diminished serum concentrations of vitamin A (retinol) and vitamin D.

Note: The use of a “dipstick” (which identifies albumin) to assess urinary protein is not an adequate substitute for urinary protein electrophoresis because individuals with DBS spill protein moieties with molecular weights lower than that of albumin.

Molecular Genetic Testing

Gene. LRP2 (low-density lipoprotein receptor-related protein 2) is the only gene currently known to be associated with DBS.

Clinical and research testing

Table 1. Summary of Molecular Genetic Testing Used in Donnai-Barrow Syndrome

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
LRP2Sequence analysisSequence variants 2, 3100%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Kantarci et al [2007], Kantarci et al [2008]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband with clinical characteristics of DBS:

  • Brain MRI scan for identification of partial or complete agenesis of corpus callosum
  • Urinary protein electrophoresis to identify low molecular-weight proteins and characteristic banding pattern.

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. However, urine collected from several proven heterozygotes demonstrated higher-than-normal total protein [Kantarci et al 2007].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

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

Clinical Description

Natural History

Information on long-term follow-up and natural history of Donnai-Barrow syndrome (DBS) is limited to a few individuals because many affected pregnancies are interrupted or result in perinatal death secondary to congenital malformations. The following information is based on the citations Holmes & Schepens [1972], Donnai & Barrow [1993], Schowalter et al [1997], Devriendt et al [1998], Avunduk et al [2000], Chassaing et al [2003], Chen [2007], Kantarci et al [2007], and Patel et al [2007], and reviewed in Pober et al [2009] unless otherwise indicated.

Relatively high birth weight (~4 kg) has been recorded in several cases. Urgent surgical treatment of diaphragmatic hernia and/or omphalocele in newborns with these complications and postoperative care dominates the early weeks.

Progressive visual loss resulting in legal blindness is common and seemingly the result of severe myopia and an attendant risk for retinal detachment, although prompt treatment can improve the chances of useful vision. Prophylactic treatment with peripheral barrier photocoagulation to prevent retinal detachment has been successful in several cases. Progressive retinal dystrophy has been observed in a few individuals; the exact nature and rate of progression of the retinal dystrophy remain to be determined.

Sensorineural hearing loss is universal. Some individuals have useful hearing with hearing aids and a few have received cochlear implants. However, two long-term survivors (ages 15 and 21 years) have profound hearing loss (see Deafness and Hereditary Hearing Loss Overview for definitions).

Motor milestones are only slightly delayed and most children become continent.

No formal studies of intellectual functioning exist, but available data suggest that all individuals with DBS have intellectual disabilities of varying degrees ranging from mild to moderate. Formal assessment is difficult because of the severe vision and hearing deficits. The oldest individual known to have DBS is age 21 years and attends a college with special provision for his hearing and vision problems. He has no speech but communicates using British Sign Language. He can dress himself and do tasks such as keep his room tidy, make his bed, and operate a microwave and a DVD player. He takes part in supported employment and enjoys mailing and labeling tasks. He enjoys social activities and going to restaurants although he still requires some assistance with cutting food.

The presence of additional brain anomalies, such as periventricular nodular heterotopia and abnormalities of gyral patterns, is increasingly appreciated.

Involvement of other organ systems (e.g., ventriculoseptal defect [VSD] in the cardiovascular system and bicornuate uterus in the genitourinary system) has been reported but is rare. The prevalence of such defects may be under-estimated because of limited examination of fetuses with DBS and of affected infants who died in the neonatal period. One individual with focal segmental glomerulosclerosis has been reported; whether this finding is coincidental or a rare manifestation of DBS is presently unknown [Shaheen et al 2010].

General health in childhood and adolescence is good although several individuals have developed a seizure disorder in adolescence.

Pubertal development occurs at the appropriate times. Height and weight appear to be within the normal range; two of the older children are tall, with heights on the 90th centile.

Pathophysiology. Megalin has many ligands. Because individuals with DBS have absent or dysfunctional megalin, it seems likely that failure of renal reabsorption of compounds such as retinol or vitamin D could lead to serum and/or cellular deficiencies. Preliminary data from several affected individuals confirms decreased concentration of circulating retinol compared to controls [Kantarci et al 2007].

Megalin also localizes to the human brain and may be a key component in the transport of ligands across the choroid plexus and into astrocytes for neuronal development during embryogenesis. Failure of these processes may result in observed brain malformations and intellectual disabilities [Bento-Abreu et al 2008].

Evidence further suggests that dysregulation of cell growth and intraocular fluid production in the setting of megalin deficiency is the likely cause of the enlarged ocular globes and high myopia [Veth et al 2011].

Genotype-Phenotype Correlations

Currently, the phenotype cannot be predicted by the genotype. The explanation for the presence of intrafamilial phenotypic variation, which can be considerable among family members with the same genotype, is unknown [Kantarci et al 2007].

Nomenclature

The following terms should no longer be used when referring to DBS:

  • Syndrome of ocular and facial anomalies, telecanthus, and deafness
  • Holmes-Schepens syndrome
  • Diaphragmatic hernia-exomphalos-hypertelorism syndrome
  • Diaphragmatic hernia-hypertelorism-myopia-deafness syndrome

Prevalence

No incidence or prevalence data are available. However, enrichment for consanguinity among parents of affected individuals suggests that mutant alleles are rare.

DBS has been reported in different ethnic groups, including northern and central European, Middle-Eastern, American of European origin, and African American. No one ethnic group predominates.

Differential Diagnosis

Donnai-Barrow syndrome (DBS) is associated with congenital diaphragmatic hernia (CDH) (see Congenital Diaphragmatic Hernia Overview).

The following syndromes include some features of DBS:

  • Pallister-Killian syndrome (12p tetrasomy mosaicism) [OMIM 601803]. Affected infants can have diaphragmatic hernia and relatively high birth weight as well as ocular hypertelorism plus a range of other structural and developmental defects.
  • Fryns syndrome comprises diaphragmatic defects, pulmonary hypoplasia, characteristic facial appearance including coarse face, and distal digital hypoplasia. A variety of other anomalies involving brain, cardiovascular system, and genitourinary system have been reported. No genetic mutation responsible for Fryns syndrome has been identified. In fact, Fryns syndrome may be etiologically heterogeneous, as some cases are seemingly autosomal recessive whereas others are caused by de novo microdeletions.
  • Chudley-McCullough syndrome [OMIM 604213] is a rare autosomal recessive disorder with characteristic features of sensorineural hearing loss, partial agenesis of the corpus callosum, arachnoid cysts, and hydrocephalus.
  • Acrocallosal syndrome [OMIM 200990] is an autosomal recessive disorder associated with macrocephaly, ocular hypertelorism, postaxial polydactyly, hallux duplication, and absence of the corpus callosum.
  • Dent disease 1, Dent disease 2, and Lowe syndrome. Affected individuals may display low molecular-weight proteinuria. Males with Lowe syndrome have a combination of bilateral dense congenital cataracts, infantile congenital hypotonia, delayed development, and proximal renal tubular transport dysfunction of the Fanconi type.
  • Craniofrontonasal syndrome [OMIM 304110], an X-linked condition resulting from EFNB1 mutations, is characterized by agenesis of the corpus callosum, congenital diaphragmatic hernia, umbilical hernia, hypertelorism, and frontal bossing.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Donnai-Barrow syndrome (DBS), the following studies are recommended:

  • Neuroimaging (preferably MRI scan)
  • Detailed ophthalmologic examination including glaucoma screening
  • Audiologic evaluation
  • Quantitative urine protein determination
  • Serum tests of renal function including blood urea nitrogen (BUN) and serum creatinine concentrations
  • Determination of circulating levels of vitamin A, vitamin D, and other regulators of calcium status
  • EEG if symptoms suggest a seizure disorder
  • Genetics consultation

Treatment of Manifestations

The following are appropriate:

  • Surgical repair of diaphragmatic hernia and postoperative assessment of respiratory function to determine if the risk for long-term respiratory problems is increased
  • Surgical repair of omphalocele

    Note: Surgical repair of omphalocele and/or diaphragmatic hernia seems to pose no greater risk than repair of these defects in children with other genetic syndromes.
  • Provision of corrective lenses for myopia; treatment of retinal detachments or glaucoma
  • Provision of appropriate hearing aids and/or cochlear implants (see Deafness and Hereditary Hearing Loss Overview for more details)
  • Education tailored to degree of intellectual, visual, and hearing disabilities
  • Antiepileptic drugs for seizures

Surveillance

Formal ophthalmic examination should be performed as soon as the diagnosis of DBS is considered. Frequent and serial monitoring is needed; the schedule should be determined by the findings present. Treatments (e.g., peripheral laser photocoagulation) may minimize the risk of retinal detachment resulting from high myopia.

Hearing evaluations should be performed as soon as the diagnosis of DBS is considered. Data on the natural history and possible progression of hearing loss are not currently available and thus no timetable for monitoring has been established.

Periodic monitoring of renal function seems prudent, based on the report of Shaheen et al [2010]. However the frequency of DBS-associated renal dysfunction is not currently known.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov 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.

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

Donnai-Barrow syndrome (DBS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are usually obligate heterozygotes with each carrying one mutant allele.
  • Paternal uniparental isodisomy for chromosome 2 accounted for homozygous LRP2 mutations in a proband whose father was heterozygous for the mutation and whose mother had two normal LRP2 alleles [Kantarci et al 2008].
  • Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects or craniofacial dysmorphology. However, urine collected from several proven heterozygotes demonstrated higher-than-normal total protein [Kantarci et al 2007]; further work will be required to determine the frequency (and clinical significance, if any) of this finding.

Sibs of a proband

  • When both parents are mutation carriers, 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.
  • Given the variability among affected sibs of the occurrence of major structural birth defects (i.e., omphalocele or CDH), the presence of one of the defects in one sib does not predict the presence of either or both in another sib.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • In the case of uniparental isodisomy, the recurrence risk for sibs of the proband is very low.
  • Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects or craniofacial dysmorphology. However, urine collected from several proven heterozygotes demonstrated higher than normal total protein [Kantarci et al 2007].

Offspring of a proband. No reports of reproduction in individuals with DBS have been published.

Other family members of a proband. When a parent of a proband is a mutation carrier, each of his/her sibs is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing of at-risk family members is possible through laboratories offering either testing for the gene of interest or custom testing.

Related Genetic Counseling Issues

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

Fetal ultrasonography. Prenatal diagnosis using ultrasound examination or fetal MRI scanning for pregnancies at increased risk for DBS can be achieved by detecting anomalies such as partial or complete agenesis of the corpus callosum, diaphragmatic hernia, omphalocele, and the characteristic facial appearance including ocular hypertelorism and prominent eyes.

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

Resources

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.

  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 800-424-3688 (toll-free); 202-387-1968
    Fax: 202-387-2193
    Email: anam@aaidd.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    #2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • CHERUBS
    The Association of Congenital Diaphragmatic Hernia Research, Awareness and Support
    3650 Rogers Road
    #290
    Wake Forest NC 27587
    Phone: 919-610-0129
    Fax: 815-425-9155
    Email: info@cdhsupport.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov

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. Donnai-Barrow Syndrome: Genes and Databases

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

Table B. OMIM Entries for Donnai-Barrow Syndrome (View All in OMIM)

222448DONNAI-BARROW SYNDROME
600073LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 2; LRP2

Molecular Genetic Pathogenesis

Donnai-Barrow syndrome (DBS) is caused by presumed loss-of-function mutations in the low-density lipoprotein receptor-related protein 2 gene (LRP2) encoding an endocytic transmembrane glycoprotein, megalin (LRP-2/gp330) [Kantarci et al 2007]. Megalin was first described as the pathogenic autoantigen of Heymann nephritis in rats. Most of the megalin-knockout mice (megalin -/-) die shortly after birth from respiratory insufficiency [Willnow et al 1996, Leheste et al 1999].

Examination of megalin-deficient mice shows forebrain anomalies including ACC and mild holoprosencephaly [Willnow et al 1996, Leheste et al 1999]. Among the few persons with DBS with detailed neuroimaging, callosal abnormalities and ocular globe abnormalities are universal, but none has shown evidence of holoprosencephaly. Periventricular nodular heterotopia and cortical patterning abnormalities in one affected individual underscore the important role of megalin in early human brain development [Kantarci et al 2007].

Megalin is not necessary in kidney development, but is required for endocytotic processes [Willnow et al 1996, Leheste et al 1999, Anzenberger et al 2006, Fisher & Howie 2006]. Megalin-deficient mice excrete low-molecular-weight plasma proteins including DBP and RBP, α1-microglobulin and odorant-binding protein in the urine [Leheste et al 1999]. Similar to megalin-deficient mice, all affected individuals with DBS and confirmed LRP2 mutations demonstrate low-molecular-weight proteinuria with increased excretion of DBP and RBP [Kantarci et al 2007].

Normal allelic variants. LRP2 spans approximately 236 kb of genomic DNA and contains 79 coding exons. The first half of exon 1 and the latter portion of exon 79 are untranslated [Hjälm et al 1996].

Pathologic allelic variants. Twelve mutations have been documented in eight affected kindreds [Kantarci et al 2007, Kantarci et al 2008]. Each kindred has unique mutations distributed throughout the gene. The homozygous or compound heterozygous LRP2 mutations found in affected individuals have been small deletions or insertions, or conserved splice-site, nonsense, and missense mutations inherited from each heterozygous carrier parent. As a rare event, one affected individual was homozygous for an LRP2 mutation resulting from paternal isodisomy of chromosome 2. Specifically, the father is a heterozygous carrier of the mutation, whereas the mother has two normal LRP2 alleles [Kantarci et al 2008].

Table 2. Selected LRP2 Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.770-2A>G
(IVS7-2A>G)
--NM_004525​.2
NP_004516​.2
c.1093C>Tp.Arg365*
c.1341+2T>G
(IVS11+2T>G)
--
c.2840-1G>A
(IVS18-1G>A)
--
c.7564T>Cp.Tyr2522His
c.8452+1G>A
(IVS44+1G>A)
--
c.8516_8519delTTTAp.Tyr2840Cysfs*67
(Val2839Valfs*67)
c.9358_9359delAGp.Ser3120Trypfs*26
c.9484_9485delGTp.Val3162Leufs*2
c.10195C>Tp.Arg3399*
c.11469_11472delTTTG 2p.Cys3823Trpfs*159
c.13139dupC
(13139insC)
p.Cys4381Metfs*12
(Pro4380Profs*12)

Note on variant classification: Variants listed in the table have been provided by the author(s). 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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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

2. The homozygous mutation caused by paternal uniparental isodisomy for chromosome 2 in an affected individual with DBS/FOAR [Kantarci et al 2008]

Normal gene product. The 600-kd megalin protein comprises 4655 amino acids. Megalin is a member of the low-density lipoprotein (LDL) receptor gene family, which is expressed predominantly in apical surface of absorptive or secretory epithelia. The large extracellular domain of the protein contains 36 cysteine-rich LDL-receptor class A (complement type) motifs, 37 LDL-receptor class B (YWTD-containing) motifs, and 17 EGF-like repeats. The single transmembrane domain of the protein is followed by a short cytoplasmic (C-terminal) domain containing two NpxY motifs. A variety of tissues including the brain, eye, renal proximal tubule, lung, intestine, uterus, oviduct, male reproductive tract, and embryonic yolk sac express megalin. Megalin binds more than 50 ligands, including lipoproteins, vitamin-binding proteins, hormones, enzymes, and immune- and stress-response-related proteins. It has been proposed that megalin interacts with the sonic hedgehog protein. Receptor-associated protein and megalin are coexpressed in different tissues during development. Megalin and a membrane receptor cubilin (gp280) share many ligands [Fisher & Howie 2006].

Abnormal gene product. The mutations in LRP2 that cause DBS are predicted to result in loss of function of the protein based on observation of similar phenotypes among all affected individuals, including those with homozygous frameshift mutations causing premature termination codons. No detailed description or explanation of the pathophysiology of the mutant protein in causing the human congenital malformations characteristic of DBS is available.

References

Literature Cited

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  2. Avunduk AM, Aslan Y, Kapicioğlu Z, Elmas R. High myopia, hypertelorism, iris coloboma, exomphalos, absent corpus callosum, and sensorineural deafness: report of a case and further evidence for autosomal recessive inheritance. Acta Ophthalmol Scand. 2000;78:221–2. [PubMed: 10794262]
  3. Bento-Abreu A, Velasco A, Polo-Hernández E, Pérez-Reyes PL, Tabernero A, Medina JM. Megalin is a receptor for albumin in astrocytes and is required for the synthesis of the neurotrophic factor oleic acid. J Neurochem. 2008;106:1149–59. [PubMed: 18466341]
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  13. Leheste JR, Rolinski B, Vorum H, Hilpert J, Nykjaer A, Jacobsen C, Aucouturier P, Moskaug JO, Otto A, Christensen EI, Willnow TE. Megalin knockout mice as an animal model of low molecular weight proteinuria. Am J Pathol. 1999;155:1361–7. [PMC free article: PMC1867027] [PubMed: 10514418]
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Suggested Reading

  1. Kantarci S, Donahoe PK. Congenital diaphragmatic hernia (CDH) etiology as revealed by pathway genetics. Am J Med Genet C Semin Med Genet. 2007;145C:217–26. [PubMed: 17436295]

Chapter Notes

Acknowledgments

We thank Dr Patricia K Donahoe for her leadership and continuous support. We also thank the many physicians who referred patients with DBS/FOAR to us. Finally, we gratefully thank all families who have participated in our study, through which we were able to find the gene responsible for DBS/FOAR.

Revision History

  • 28 June 2011 (me) Comprehensive update posted live
  • 28 August 2008 (me) Review posted live
  • 28 April 2008 (brp) Original submission
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