Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: COL4A3
Cytogenetic location: 2q36.3 Genomic coordinates (GRCh38): 2:227,164,624-227,314,792 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q36.3 | Alport syndrome 3A, autosomal dominant | 104200 | Autosomal dominant | 3 |
| Alport syndrome 3B, autosomal recessive | 620536 | 3 | ||
| Hematuria, benign familial, 2 | 620320 | Autosomal dominant | 3 |
Type IV collagen is found only in basement membranes, where it is the major structural component. COL4A3 is 1 of 6 alpha chains that form the heterotrimeric type IV collagen molecules. Tumstatin, a peptide fragment derived from the C-terminal noncollagenous (NC1) domain of COL4A3, has antiangiogenic activity. The NC1 domain of COL4A3 has also been referred to as the Goodpasture antigen, since it is the primary target of autoantibodies produced in Goodpasture syndrome (233450) (Bernal et al., 1993; Mariyama et al., 1994; Hamano and Kalluri, 2005).
Butkowski et al. (1987) identified a third alpha chain of basement membrane collagen, type IV. Studying in particular the noncollagenous part of the alpha-3(IV) chain, Saus et al. (1988) concluded that collagen IV is composed of a third chain (alpha-3) together with the 2 classical ones, alpha-1 (120130) and alpha-2 (120090). They also concluded that the epitope to which the major reactivity of autoantibodies are targeted in the glomerular basement membrane in patients with Goodpasture syndrome is localized to the NC1 domain of the alpha-3(IV) chain. See also Butkowski et al. (1989). Morrison et al. (1991) sequenced a partial cDNA encoding the COL4A3 gene.
By PCR of adult human kidney, followed by S1 nuclease mapping and primer extension of kidney and testis total RNA, Mariyama et al. (1994) obtained full-length COL4A3. The deduced 1,670-amino acid protein has a calculated molecular mass of 161.8 kD. It has a 28-amino acid leucine-rich signal peptide, followed by a 1,410-amino acid collagenous domain, and a 232-amino acid C-terminal NC1 domain. The collagenous domain begins with a 14-amino acid noncollagenous sequence that includes 4 cysteines, and the collagenous repeat gly-X-Y is interrupted 23 times by short noncollagenous sequences. Full-length COL4A3 has 5 arg-gly-asp sequences that mediate binding to integrins. COL4A3 is most similar to COL4A1 (120130) and COL4A5 (303630), indicating that it belongs to the alpha-1-like class of type IV collagen chains. Northern blot analysis detected strong expression of an approximately 8-kb COL4A3 transcript in adult kidney, skeletal muscle, and lung and in fetal kidney and lung. Expression of COL4A3 largely overlapped that of COL4A4 (120131), suggesting that expression of the 2 transcripts may be coregulated.
The Goodpasture antigen corresponds to the C-terminal NC1 domain of COL4A3, which is encoded by the last 5 exons of the COL4A3 gene. Using RT-PCR, Bernal et al. (1993) identified COL4A3 splice variants lacking 1 or 2 exons in the NC1-coding region. These variants encode identical proteins with C-terminal ends shorter than that of the full-length protein due to the introduction of a frameshift. Since the NC1 domain of COL4A3 is involved in alignment of individual alpha chains into a triple-helical structure, Bernal et al. (1993) suggested that these C-terminally truncated COL4A3 isoforms may be defective in triple-helix formation. RT-PCR revealed significant expression of COL4A3 in kidney, lung, suprarenal capsule, muscle, and spleen, with very low expression in artery, fat, pericardium, and peripheral nerve. Although the COL4A3 splice variants were present in these tissues, the full-length form was most abundant. PCR analysis of kidney cortex biopsied from a Goodpasture patient revealed a small but reproducible decrease in the ratio of full-length to variant transcripts compared with normal kidney.
Feng et al. (1994) also identified COL4A3 splice variants lacking NC1-coding exons, resulting in proteins with alternative C termini. Ribonuclease protection assays revealed changes in expression of full-length and variant transcripts during fetal kidney development and in adult human kidney.
By microarray analysis, Jun et al. (2001) demonstrated expression of the COL4A3 gene in human donor corneas.
Heidet et al. (2001) determined that the COL4A3 gene contains 52 exons and spans over 88 kb.
Mariyama et al. (1994) determined that the COL4A3 gene has 2 closely spaced major transcription start sites.
Momota et al. (1998) reported that the COL4A3 and COL4A4 genes are on opposite strands of chromosome 2 and are transcribed in opposite directions. The first exon of COL4A3, which contains the translation start site, is separated from 2 alternative first exons of COL4A4 by 372 and 5 bp, respectively. The promoter region, which is shared by both genes, is composed of dense CpG dinucleotides, GC boxes, CTC boxes, and a CCAAT box, but not a TATA box.
Morrison et al. (1991) assigned a partial COL4A3 cDNA to chromosome 2q35-q37 by a combination of somatic cell hybrid studies and in situ hybridization. Turner et al. (1992) localized the COL4A3 gene to chromosome 2q36-q37 by analysis of somatic cell hybrids and by in situ hybridization. Momota et al. (1998) reported that the COL4A3 and COL4A4 genes are arranged in a head-to-head fashion on chromosome 2.
Wieslander et al. (1984, 1985) presented immunochemical evidence that the Goodpasture antibodies react with collagenase-resistant parts of the type IV collagen molecule. About 5% of cases of glomerulonephritis are mediated by autoantibodies to glomerular basement membrane (GBM). Most of these patients present with Goodpasture syndrome (glomerulonephritis and pulmonary hemorrhage). Butkowski et al. (1987) localized the Goodpasture epitope to a novel chain of type IV collagen composed of 3 distinctive subunits--M1, M2*, and M3. The Goodpasture epitope was found to be situated exclusively on M2*. Turner et al. (1992) demonstrated that the Goodpasture antigen is the alpha-3 chain of type IV collagen (COL4A3; 120070).
Although the primary defect in Alport syndrome (301050) involves the COL4A5 gene (303630), the pathogenesis of the syndrome probably involves type IV collagen molecules containing the alpha-3(IV) chain: Hudson et al. (1992) demonstrated that the Goodpasture autoantigen is the target alloantigen in posttransplant anti-GBM (glomerular basement membrane) nephritis in patients with Alport syndrome. Kalluri et al. (1994) further confirmed the unique capacity of alpha-3(IV)NC1 dimer from bovine kidney to engage aberrantly the immune system of rabbits to respond to self, mimicking the organ-specific form of the human disease, whereas the other chains of type IV collagen were nonpathogenic. The hexamer of alpha3-(IV) NC1 was nonpathogenic, suggesting the exposure of a pathogenic epitope upon dissociation of hexamer into dimers. Exposure of the pathogenic epitope by infection or organic solvents, events that are thought often to precede Goodpasture syndrome, may be a principal factor in the etiology of the disease.
Krafchak et al. (2005) detected a complex (core plus secondary) binding site for TCF8 (189909) in the promoter of the COL4A3 gene, and presented immunochemical evidence of ectopic expression of COL4A3 in corneal endothelium of a proband of a family with posterior polymorphous corneal dystrophy-3 (PPCD3; 609141). The authors suggested that the implication of COL4A3 as a target of TCF8 regulation identifies a possible shared molecular component of disease etiology for PPCD and Alport syndrome.
Tumstatin
Maeshima et al. (2000) termed the noncollagenous I domain of the alpha-3 chain of type IV collagen (COL4A3) 'tumstatin.' This domain had been discovered to possess a C-terminal peptide sequence (amino acids 185 to 203) that inhibits melanoma cell proliferation by Han et al. (1997). Maeshima et al. (2000) identified the antiangiogenic capacity of this domain using several in vitro and in vivo assays. Tumstatin inhibited in vivo neovascularization in matrigel plug assays and suppressed tumor growth of human renal cell carcinoma and prostate carcinoma in mouse xenograft models associated with in vivo endothelial cell-specific apoptosis. The antiangiogenic activity was localized to amino acids 54-132 using deletion mutagenesis. Shahan et al. (1999) identified amino acids 185-203 of tumstatin as a ligand for the alpha-V-beta-3 integrin (193210, 173470). Maeshima et al. (2000) found a distinct additional RGD-independent alpha-V-beta-3 integrin binding site within amino acids 54 to 132 of tumstatin. Maeshima et al. (2001) demonstrated that tumstatin peptides can inhibit proliferation of endothelial cells in the presence of vitronectin (193190), fibronectin (135600), and collagen I (see 120150). The antiangiogenic activity of tumstatin is localized to a 25-amino acid region (69-88) of tumstatin and is independent of disulfide bond linkage. Maeshima et al. (2002) demonstrated that tumstatin functions as an endothelial cell-specific inhibitor of protein synthesis. Through a replicative interaction with alpha-V-beta-3 integrin, tumstatin inhibits activation of focal adhesion kinase (FAK; 600758), phosphatidylinositol 3-kinase (see 171834), protein kinase-B (164730), and mammalian target of rapamycin (601231). Maeshima et al. (2002) further demonstrated that tumstatin prevents the dissociation of eukaryotic initiation factor 4E protein (133440) from 4E-binding protein-1 (602223). Maeshima et al. (2002) concluded that their results establish a role for integrins in mediating cell-specific inhibition of cap-dependent protein synthesis and suggest a potential mechanism for tumstatin's selective effects on endothelial cells.
Tumstatin and endostatin, 2 inhibitors of angiogenesis, derive from the precursor human collagen molecules COL4A3 and COL18A1 (120328), respectively. Although both of these inhibitors are NC1 domain fragments of collagens, they share only 14% amino acid homology. Sudhakar et al. (2003) evaluated the functional receptors, mechanism of action, and intracellular signaling induced by these 2 collagen-derived inhibitors. Tumstatin prevents angiogenesis through inhibition of endothelial cell proliferation and promotion of apoptosis with no effect on migration, whereas endostatin prevents endothelial cell migration with no effect on proliferation. Sudhakar et al. (2003) demonstrated that tumstatin binds to alpha-V-beta-3 integrin in a vitronectin/fibronectin/RGD cyclic peptide-independent manner, whereas endostatin competes with fibronectin/RGD cyclic peptide to bind alpha-5-beta-1 integrin (135620, 135630). The activity of tumstatin is mediated by alpha-V-beta-3 integrin, whereas the activity of endostatin is mediated by alpha-5-beta-1 integrin. Because of the distinct properties of tumstatin and endostatin, indicating their diverse antiangiogenic actions, the authors suggested the 2 be combined for targeting tumor angiogenesis.
Eikesdal et al. (2008) showed that leu78, val82, and asp84 of tumstatin were essential for its antiangiogenic activity. However, mutation of all 3 of these residues had only a modest effect on binding to cell surface alpha-V-beta-3 integrin.
Hellmark et al. (1999) provided, for the first time, the molecular characterization of a single immunodominant conformational epitope recognized by pathogenic autoantibodies in a human autoimmune disease. Identified in Goodpasture disease, it represented the basis for the development of new epitope-specific strategies in the treatment of that disorder. Hellmark et al. (1999) identified the epitope by replacing single residues of the COL4A3 chain with the corresponding amino acids from the nonreactive COL4A1 gene. Replacement mutations were identified that completely destroyed the Goodpasture epitope in the COL4A3 gene. The substitution of 9 discontinuous positions in the COL4A1 noncollagenous domain with amino acid residues from the COL4A3 chain resulted in the recombinant construct that was recognized by all patients' sera but by none of the sera from healthy controls.
In a patient with deletion of 2q35-q36, Pasteris et al. (1992) demonstrated that the COL4A3 gene was deleted, as was also the PAX3 (606597) gene, which was situated proximally. The deletion was estimated to be less than 12.5 megabases.
Autosomal Recessive Alport Syndrome 3B
In 2 families segregating autosomal recessive Alport syndrome (ATS3B; 620536), Mochizuki et al. (1994) demonstrated homozygous mutations in the COL4A3 gene (120070.0001-120070.0002).
Lemmink et al. (1994) demonstrated compound heterozygous mutation in the COL4A3 gene (see, e.g., 120070.0002 and 120070.0003) as the basis of autosomal recessive Alport syndrome.
Lemmink et al. (1997) reviewed the clinical spectrum of type IV collagen mutations associated with renal disease. They found reports of 6 mutations in the COL4A3 gene but commented that few patients and only a small part of the gene had been studied. Patients were either homozygous or compound heterozygous for the mutations, and parents were asymptomatic carriers. All 6 COL4A3 mutations created a premature stop codon.
Hudson et al. (2003) reviewed the biology of type IV collagen and its relationship to Alport syndrome and the autoimmune disorder Goodpasture syndrome (233450). They diagrammed and reviewed the distribution and switches of collagen IV networks in development of the renal glomerulus.
Autosomal Dominant Alport Syndrome 3A
In affected members of a family with autosomal dominant Alport syndrome (ATS3A; 104200) reported by Jefferson et al. (1997), van der Loop et al. (2000) identified a heterozygous mutation in the COL4A3 gene (120070.0009). The mutation resulted in a splice site mutation and a mutant protein with a deletion in the collagenous domain. The mutation was found in all 6 affected individuals and in none of 8 unaffected individuals. Since the noncollagenous domain remained intact, this mutant chain may be incorporated and distort the collagen triple helix, causing a dominant effect. The finding of a COL4A3 mutation in autosomal dominant Alport syndrome completed the broad spectrum of type IV collagen mutations, ranging from no effect at all and familial benign hematuria to mild autosomal dominant and severe autosomal recessive Alport syndrome.
Evidence of Digenic Inheritance in Alport Syndrome
Using massively parallel sequencing, Mencarelli et al. (2015) identified 11 patients with Alport syndrome who had pathogenic mutations in 2 of the 3 collagen IV genes. Seven patients had a combination of mutations in COL4A3 and COL4A4 (120131), whereas 4 patients had 1 or 2 mutations in COL4A4 associated with mutation in COL4A5 (303630). In no case were there simultaneous COL4A3 and COL4A5 mutations. Altogether, 23 unique mutations were found, including 7 in COL4A3, 12 in COL4A4, and 4 in COL4A5. The mutations involved all domains of the collagen molecules, although the majority of missense mutations (11 of 13) affected the triple-helical collagenous domain, and 11 missense mutations substituted a critical glycine residue in this domain. Thirteen mutations had been previously reported and 10 were novel.
Benign Familial Hematuria
In 2 unrelated families with benign familial hematuria (BFH2; 620320), Badenas et al. (2002) identified 2 different heterozygous missense mutations in the COL4A3 gene (120070.0007 and 120070.0008, respectively) affecting the collagenous domain of the protein.
Associations Pending Confirmation
For discussion of a possible association between variation in the COL4A3 gene and keratoconus, see KTCN1 (148300).
MacDonald et al. (2006) showed that the alpha-3(IV) chain is not present in C. elegans or Drosophila melanogaster, but is present in Danio rerio (zebrafish). However, zebrafish alpha-3(IV)NC1 does not bind Goodpasture autoantibodies. There also was complete absence of autoantibody binding to recombinant zebrafish alpha-3(VI)NC1. It appeared that evolutionary alteration of electrostatic charge and polarity due to the emergence of critical serine, aspartic acid, and lysine residues, accompanied by the loss of asparagine and glutamine, contributed to the emergence of the 2 major Goodpasture epitopes on the human alpha-3(IV)NC1 domain, as it evolved from Danio rerio over 450 million years.
Canine X-linked hereditary nephritis is an animal model for human X-linked hereditary nephritis (Alport syndrome) (301050) characterized by the presence of a premature stop codon in the alpha-5 chain of collagen type IV. Thorner et al. (1996) examined expression of the canine collagen type IV genes in the kidney. They detected alpha-3, alpha-4 (120131), and alpha-5 chains in the noncollagenous domain of type IV collagen isolated from normal dog glomeruli but not in affected dog glomeruli. In addition to a significantly reduced level of COL4A5 gene expression (approximately 10% of normal), expression of the COL4A3 and COL4A4 genes was also decreased to 14-23% and 11-17%, respectively. These findings suggested to Thorner et al. (1996) a mechanism which coordinates the expression of these 3 basement membrane proteins.
Cosgrove et al. (1996) produced a mouse model for the autosomal form of Alport syndrome by a COL4A3 knockout. The mice developed progressive glomerulonephritis with microhematuria and proteinuria. End-stage renal disease developed at about 14 weeks of age. Transmission electron microscopy (TEM) of glomerular basement membranes (GBM) during development of renal pathology revealed focal multilaminated thickening and thinning beginning in the external capillary loops at 4 weeks and spreading throughout the GBM by 8 weeks. By 14 weeks, half of the glomeruli were fibrotic with collapsed capillaries. Immunofluorescence analysis of the GBM showed the absence of type IV collagen alpha-3, alpha-4, and alpha-5 chains and a persistence of alpha-1 and alpha-2 chains, which are normally localized to the mesangial matrix. Northern blot analysis using probes specific for the collagen chains demonstrated the absence of COL4A3 in the knockout, whereas mRNAs for the remaining chains were unchanged. The progression of Alport renal disease was correlated in time and space with the accumulation of fibronectin, heparan sulfate proteoglycan, laminin-1 (see 150320), and entactin (131390) in the GBM of the affected animals.
Hamano et al. (2002) showed that Col4a3-deficient mice had normal expression of podocyte- and slit diaphragm-associated proteins until 4 weeks after birth, despite significant structural defects in the glomerular basement membrane. At week 5, there were alterations within the slit diaphragm, podocyte effacement, and altered expression of nephrin (602716), a slit diaphragm-associated protein. Hamano et al. (2002) concluded that defects in glomerular basement membrane proteins lead to an insidious plasma protein leak, while breakdown of the slit diaphragms leads to precipitous plasma protein leak.
Lu et al. (1999) generated the transgenic mouse line OVE250 by microinjection of the 4.1-kb tyrosinase minigene construct TyBS into 1-cell embryos of the inbred albino strain FVB/N. Mice homozygous for the transgenic insertion exhibited severe progressive glomerulonephritis, resembling the Alport syndrome in man. The injected minigene construct created a mutation at the site of insertion on mouse chromosome 1, leading to a deletion in the Col4a3 and Col4a4 head-to-head pair region, including exons 1 through 12 of the Col4a4 gene, exons 1 and 2 of the adjacent Col4a3 gene, and the intergenic promoter region. Transcripts of Col4a3 and Col4a4 were undetectable in the mutant kidney, and both proteins were missing from the glomerular basement membrane. This animal model of human Alport syndrome, designated Col4del3-4, lacks both alpha-3 and alpha-4 chains of collagen IV.
In family VB with autosomal recessive Alport syndrome (ATS3B; 620536), Mochizuki et al. (1994) demonstrated homozygosity for a 5-bp (CTTTT) deletion in the COL4A3 gene, causing a frameshift and chain termination after 33 amino acids of the NC1 domain. The female proband had sensorineural deafness, hematuria from 4 years of age, and typical ultrastructural lesions of Alport syndrome on electron microscopy of renal biopsy. Hemodialysis was started at age 9. Renal allograft was received at age 10, following which she developed anti-GBM nephritis. In a competitive ELISA, binding of the patient's serum was inhibited by increasing concentrations of Goodpasture sera which contains autoantibodies directed toward the NC1 domain of COL4A3. The patient's brother had hematuria, deafness, and deteriorating renal function. The parents were asymptomatic. They were not known to be related, but their ancestors originated from the same small village in the Netherlands.
In a review of type IV collagen mutations, Lemmink et al. (1997) stated that this mutation was deletion of 5 bp after nucleotide 4414. The deletion caused a frameshift after leu1474 with a stop 33 codons downstream.
In a Belgian girl (family DU), born of consanguineous parents, with autosomal recessive Alport syndrome (ATS3B; 620536), Mochizuki et al. (1994) identified a homozygous C-to-T transition in exon 5 of the COL4A3 gene, counting from the 3-prime end (Quinones et al., 1992). This mutation replaced an arginine codon with a stop codon in the NC1 domain, shortening the alpha-3(IV) chain by 190 amino acids; it was expected to disrupt 11 of the intermolecular disulfide bonds that stabilize the homodimerization of NC1 domains. The patient was found to have proteinuria and microhematuria at age 7, resulting in end-stage renal disease by age 11. At age 11, she had renal transplant from her mother, and had not developed rejection or anti-GMB nephritis by age 16. At age 13, an audiogram showed bilateral sensorineural hearing loss. Both unaffected parents had normal renal function and urinalysis. In a catalog of COL4A3 mutations causing autosomal recessive Alport syndrome, Lemmink et al. (1997) stated that this mutation was an arg1481-to-ter (R1481X) substitution caused by a a C-to-T transition at nucleotide 4441.
Lemmink et al. (1997) noted that the compound heterozygous mutations previously identified in a patient with autosomal recessive Alport syndrome and designated arg43-to-ter and ser86-to-ter by Lemmink et al. (1994) were in fact R1481X and S1524X (120070.0003).
Lemmink et al. (1997) demonstrated that a patient with autosomal recessive Alport syndrome (ATS3B; 620536) was compound heterozygous for mutations in the COL4A3 gene: R1481X (120070.0002) and a C-to-G transversion at nucleotide 4559 resulting in a ser1524-to-ter (S1524X) substitution. These mutations had previously been reported as R43X and S86X by Lemmink et al. (1994).
In the process of screening the illegitimate transcripts of COL4A3 in lymphocytes from a patient with autosomal recessive Alport syndrome (ATS3B; 620536), Knebelmann et al. (1995) discovered an antisense Alu sequence that had been spliced into the mature transcript after a G-to-T transversion activated a cryptic splice site located in the Alu element within intron V. The resultant 74-bp insertion was at the junction of exons IV or V and VI in the final transcript. This was the first observation of a splicing abnormality in the COL4A3 gene in autosomal recessive Alport syndrome. The precise mutation involved the insertion of an abnormally spliced intron 5 fragment (Finielz et al., 1998). This intron 5 mutation was found in 4 families in Reunion Island. In 1 family, 3 patients, all male, were involved. Two were placed on hemodialysis for end-stage renal disease at ages 28 and 26; the third, aged 13, had normal serum creatinine concentration values. All 3 patients had hearing impairment but no ocular lesions. The 3 other families from a different town had discovery of Alport syndrome at earlier ages ranging from 3 to 13 years on the basis of macroscopic hematuria and/or proteinuria, and in only 1 case was deafness evident. Males and females seemed to be equally involved (3 boys, 3 girls). End-stage renal failure occurred earlier (ages 14, 14, 18, and 15), unrelated to sex. Auditory impairment was a constant feature; ocular impairment involved 1 patient only. Undefined environmental factors or phenotype-modulating genes (around the assay genes) were hypothesized.
In a family (HFB-1) with benign familial hematuria (BFH2; 620320), Badenas et al. (2002) identified a mutation in exon 36 of the COL4A3 gene that resulted in a gly1015-to-glu (G1015E) amino acid substitution in the collagenous domain of the protein.
In a family (HFB-2) with benign familial hematuria (BFH2; 620320), Badenas et al. (2002) identified a mutation in exon 35 of the COL4A3 gene that resulted in a gly985-to-val (G985V) amino acid substitution in the collagenous domain of the protein.
In affected members of a family with autosomal dominant Alport syndrome (ATS3A; 104200) reported by Jefferson et al. (1997), van der Loop et al. (2000) identified a heterozygous G-to-A transition in the last nucleotide of exon 21 of the COL4A3 gene. Although the change would predict a gly493-to-ser (G493S) substitution, mRNA analysis indicated that the mutation causes a splice site mutation, resulting in the skipping of exon 21 and a mutated chain that lacks 55 amino acids in the collagenous domain. The mutation was found in all 6 affected individuals and in none of 8 unaffected individuals. Since the noncollagenous domain is intact, this mutant chain may be incorporated and distort the collagen triple helix, causing a dominant effect. The finding of a COL4A3 mutation in autosomal dominant Alport syndrome completed the broad spectrum of type IV collagen mutations.
In a mother and daughter with autosomal dominant Alport syndrome (ATS3A; 104200), Heidet et al. (2001) identified a heterozygous 3499G-A transition in exon 40 of the COL4A3 gene, resulting in a gly1167-to-arg (G1167R) substitution. The daughter developed end-stage renal failure at age 23 years. Her mother had microscopic hematuria and proteinuria, but still had normal renal function at age 52 years, although renal biopsy showed thinning of and splitting of the glomerular basement membrane.
In 3 sisters, born of unrelated parents of Ashkenazi Jewish descent, with autosomal recessive Alport syndrome (ATS3B; 620536), Webb et al. (2014) identified a homozygous 24-bp deletion (c.40_63del, NM_000091.4) in the COL4A3 gene, resulting in an in-frame deletion of 8 amino acids. The mutation, which was found by linkage analysis followed by candidate gene sequencing, segregated with the disorder in the family. Population analysis yielded a carrier frequency of 0.55% among Ashkenazi Jewish individuals, and haplotype analysis indicated a founder effect. Functional studies of the variant were not performed, but the parents were unaffected, suggesting that heterozygosity for this mutation does not predispose to disease.
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