Alternative titles; symbols
HGNC Approved Gene Symbol: COL4A5
Cytogenetic location: Xq22.3 Genomic coordinates (GRCh38): X:108,439,838-108,697,545 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq22.3 | Alport syndrome 1, X-linked | 301050 | X-linked dominant | 3 |
Hostikka et al. (1990) identified a distinct type IV collagen alpha chain, which they referred to as alpha-5. From analysis of cDNA clones, they found that the collagenous Gly-Xaa-Yaa repeat sequence has 5 'imperfections' that coincide with those in the corresponding portion of the alpha-1(IV) chain. The noncollagenous (NC) domain has 12 conserved cysteine residues and 83% and 63% sequence identity to the NC portions of the alpha-1(IV) (120130) and alpha-2(IV) (120090) chains. Antiserum against an alpha-5(IV) synthetic peptide stained a polypeptide chain of about 185 kD by immunoblot analysis. Immunolocalization in the human kidney was almost completely restricted to the glomerulus.
Zhou et al. (1992) found that the cDNA for the COL4A5 gene predicts a translation product with 1,685 amino acid residues: a 26-residue signal peptide, a 1,430-residue collagenous domain starting with a 14-residue noncollagenous sequence, and a gly-Xaa-Yaa-repeat sequence interrupted at 22 locations, followed by a 229-residue carboxyl-terminal noncollagenous domain. The calculated molecular mass of the mature chain is 158,303 Da.
Zhou et al. (1991) described the 3-prime half of the human COL4A5 gene, including the intron-exon structure. They determined the sequence of the 19 3-prime-most exons and their flanking sequences from genomic phage clones, with the exception of exon 15, which was sequenced after amplification from genomic DNA by PCR. The exon sizes in the 3-prime half of the gene bear a remarkable similarity to those observed in the alpha-1(IV) chain.
Vetrie et al. (1992) constructed a 2.4-Mb long-range restriction map around the COL4A5 gene. High-resolution PFGE mapping with the rare-cutting enzyme XhoI showed that the gene is at least 110 kb long, one of the largest collagen genes characterized to date.
Zhou et al. (1994) determined that the COL4A5 gene contains 51 exons.
By Southern analysis of somatic cell hybrids and by in situ hybridization, Hostikka et al. (1990) assigned the COL4A5 locus to Xq22.
SLITs (see SLIT1; 603742) are secreted glycoproteins that bind and activate ROBO receptors (see ROBO1; 602430) and function in axon guidance during development. Using a zebrafish model, Xiao et al. (2011) showed that Col4a5 on the surface of the tectum basement membrane bound Slit1 and guided retinal ganglion cell axons expressing Robo2 (602431).
Lemmink et al. (1997) gave a comprehensive review of the clinical manifestations associated with mutations in type IV collagen genes. The features vary from the severe clinically and genetically heterogeneous renal disorder Alport syndrome (see, e.g., 301050), to autosomal dominant familial benign hematuria (BFH; 141200). The authors stated that more than 160 different mutations had been identified in the COL4A5 gene. To the previously reported COL4A5 mutations, Lemmink et al. (1997) added 8 new ones identified in their group of patients with X-linked Alport syndrome (ALS1; 301050). The spectrum of mutations was broad and provided insight into the clinical variability of Alport syndrome with respect to age at renal failure and accompanying features.
X-Linked Alport Syndrome
Because X-linked Alport syndrome (ALS1; 301050) had been mapped to Xq22, where the COL4A5 gene maps, Hostikka et al. (1990) sought a defect in the COL4A5 gene; no major rearrangement was found in a single male patient. However, Barker et al. (1990) clinched the association between the COL4A5 gene and at least 1 form of Alport syndrome by demonstrating 3 structural aberrations in the COL4A5 gene (303630.0001-303630.0003) in separate families with Alport syndrome in Utah: an intragenic deletion, a PstI site variant, and an uncharacterized abnormality.
Antignac et al. (1994) tested the COL4A5 gene in 88 unrelated male patients with X-linked Alport syndrome for major gene rearrangements by Southern blot analysis using COL4A5 cDNA probes. They detected 14 different deletions, providing a 16% deletion rate in that patient population. The deletions were dispersed all over the gene with different sizes ranging from 1 kb to the complete absence of the gene (more than 250 kb) in 1 patient. In 4 patients with intragenic deletions, absence of the alpha-3(IV) chain in the glomerular basement membrane was demonstrated by immunohistochemical methods. This finding supported the hypothesis that abnormalities of the alpha-5(IV) chain may prevent normal incorporation of the alpha-3(IV) chain into the glomerular basement membrane. Direct sequencing of cDNA amplified from lymphoblast mRNA of 4 patients with internal gene deletions, using appropriate combinations of primers amplifying across the predicted boundaries of the deletions, allowed Antignac et al. (1994) to determine the effect of genomic rearrangements on the transcripts and, by inference, on the alpha-5(IV) chain. Regardless of the extent of deletion and of the putative protein product, the 14 deletions occurred in patients with juvenile-type Alport syndrome.
Lemmink et al. (1994) stated that more than 60 different mutations had been detected in the COL4A5 gene in Alport patients.
Knebelmann et al. (1996) screened 48 of the 51 exons of the COL4A5 gene by SSCP analysis and identified 64 mutations and 10 sequence variants among 131 unrelated patients with X-linked Alport syndrome. They noted that the mutation detection rate was approximately 50%. Knebelmann et al. (1996) hypothesized that this incomplete detection could be in part due to sensitivity of the SSCP technique, or to lack of detection of splice site mutations because of primer design. They noted that intronic changes such as inversions (shown to be pathogenic in hemophilia; see 306700 and Naylor et al., 1993) and unstable trinucleotide repeat expansions (shown to be pathogenic in Friedreich ataxia; see 229300 and Campuzano et al., 1996) had not been ruled out as disease-causing changes in COL4A5.
The large multiexonic COL4A5 gene had been difficult to screen; several studies detected only approximately 50% of the mutations in this gene. A partial explanation for this was suggested by the findings of King et al. (2002): they identified 3 novel intronic mutations that demonstrated that single base changes deep within introns can, and do, cause X-linked Alport syndrome. One mutation created a new donor splice site within an intron resulting in the inclusion of a novel in-frame cryptic exon; a second mutation resulted in a new exon splice enhancer sequence (ESE) that promoted splicing of a cryptic exon containing a stop codon; a third mutation was a base substitution within the polypyrimidine tract that precedes the acceptor splice site that resulted in exon skipping. All 3 cases would have been missed using an exon-by-exon DNA screening approach.
Contiguous Gene Deletion Syndromes Involving COL4A5
Antignac et al. (1992, 1992) presented evidence that the syndrome of diffuse esophageal leiomyomatosis and Alport syndrome (308940), which had been reported in 24 patients, most of whom also suffered from congenital cataract, represents a contiguous gene deletion syndrome. They found patients with deletion in the 5-prime part of the COL4A5 gene, extending upstream for at least 700 bp.
Zhou et al. (1993) demonstrated that the leiomyomatosis-nephropathy syndrome represents a contiguous gene syndrome due to deletions that disrupt the COL4A5 and COL4A6 (303631) genes.
Evidence for Digenic Inheritance
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 (120070) and COL4A4 (120131), whereas 4 patients had 1 or 2 mutations in COL4A4 associated with mutation in COL4A5. In no case were there simultaneous COL4A3 and COL4A5 mutations. For each of these 11 probands, between 1 and 12 family members were recruited, for an average of 4 members per family (56 individuals ranging from 5-80 years). 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. Among the 8 patients with mutations in COL4A4 and COL4A5 (4 probands and 4 family members), the phenotypes included hematuria with proteinuria in 6 individuals and end-stage renal disease in 2 individuals. In 1 family, the proband carried 2 in trans mutations in COL4A4 in addition to the mutation in COL4A5.
Canine X-linked hereditary nephritis is an animal model for Alport syndrome. Zheng et al. (1994) used information on the nucleotide sequence for human COL4A5 cDNA to construct a set of primers for dog kidney cDNA. They found that the nucleotide sequence encoding the noncollagenous domain NC1 hybridized to the human X chromosome and was 93% identical at the DNA level and 97% identical at the protein level to the human NC1 domain. Sequence analysis demonstrated a G-to-T transversion in affected dogs, changing a codon in exon 35 from GGA (glycine) to a stop codon (TGA). Transcription of the COL4A5 gene was reduced by a factor of approximately 10 in the affected dog.
Thorner et al. (1996) examined expression of the canine collagen type IV genes in the kidney. They detected alpha-3 (120070), 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.
In Utah kindred EP with Alport syndrome (ALS1; 301050), Barker et al. (1990) found deletion of the portion of the COL4A5 gene containing exons 5 through 10 (exons having been numbered with exon 1 being the most 3-prime exon). The deafness in the proband with the large deletion was among the most profound encountered in Alport kindreds, implying that the severity of deafness is correlated with the severity of the defect in COL4A5.
In the historic kindred P in Utah studied by Perkoff et al. (1951, 1958) and later by Hasstedt and Atkin (1983), Barker et al. (1990) demonstrated that a PstI site variant segregated in complete linkage with the presence or absence of the Alport phenotype (ALS1; 301050). All 23 gene-carrying mothers were heterozygous; a total of 45 sons showed complete linkage. In an addendum, Barker et al. (1990) stated that by PCR amplification and DNA sequencing, the PstI variant had been shown to be due to a single basepair change that converted a highly conserved cysteine codon in the noncollagenase (NC) domain to a codon for serine (C108S). (The NC domain of glomerular basement membrane type IV collagen has been shown to be absent or altered in Alport syndrome on the basis of studies with antibodies directed against this portion of the molecule.) Zhou et al. (1991) described the generation of a new BglII site and showed that the cys-to-ser change occurred in the third to the last exon. Boye et al. (1991) commented that the defect had been defined as a G-to-C transition in exon 3 that created both a PstI and a BglII site.
Through an analysis of the 3-prime end of the COL4A5 gene using 3 cDNA clones, Boye et al. (1991) found mutations in 3 of 38 patients with Alport syndrome (ALS1; 301050). One patient had a complex insertion/deletion mutation. Using pulsed field gel electrophoresis, Vetrie et al. (1992) found that the mutation involved an intragenic insertion of 10 to 15 kb and an extragenic deletion of 40 kb, with an overall deletion of 25 kb.
Through an analysis of the 3-prime end of the COL4A5 gene using 3 cDNA clones, Boye et al. (1991) found mutations in 3 of 38 patients with Alport syndrome (ALS1; 301050). One patient had a deletion of at least 35 kb. Using pulsed field gel electrophoresis, Vetrie et al. (1992) found that the mutation involved deletion of 450-kb, including approximately 12 kb of the 3-prime end (exons 1-6).
In a 12-year-old Italian boy with Alport syndrome (ALS1; 301050), Renieri et al. (1992) found a large deletion (more than 38 kb) that included the 5-prime part of the COL4A5 gene.
In 1 of 20 Danish kindreds with Alport syndrome (ALS1; 301050), Zhou et al. (1992) found a GGC-to-GAC mutation changing glycine-1143 to aspartate. Substitution of any amino acid for glycine-1143, located in the collagenous domain of the alpha-5(IV) chain, would be expected to interfere with the maintenance of the triple-helical conformation of the collagen molecule and, in turn, weaken the glomerular basement membrane framework, leading to increased permeability. The proband was a 27-year-old male who developed hematuria in childhood and terminal renal failure at the age of 25 years. He had no hearing loss or ocular lesions. Electron microscopy demonstrated splitting of the lamina densa of the glomerular basement membrane. The proband's mother had had persistent microscopic hematuria since the age of 40 years but no other manifestations.
In a kindred with many members affected with adult-type X-linked Alport syndrome (ALS1; 301050), Knebelmann et al. (1992) found by Southern blot analysis a loss of an MspI restriction site in the COL4A5 gene. Direct sequencing of cDNA demonstrated a gly325-to-arg (G325R) mutation. Knebelmann et al. (1992) commented that this type of mutation in the COL1A1 and COL1A2 genes is often associated with osteogenesis imperfecta.
In a patient with severe Alport syndrome (ALS1; 301050) and end-stage renal disease (ESRD) by age 17, accompanied by deafness, Smeets et al. (1992) found deletion of exons encoding the noncollagenous domain and part of the collagenous region of the collagen IV alpha-5 chain. Transplantation with the kidney of an unrelated donor was followed by rapidly progressive anti-glomerular basement membrane nephritis, leading to loss of the transplant almost 7 months after grafting. His affected maternal grandfather died from renal failure at the age of 26 years. The deletion appeared to be present in heterozygous form in the mother and sister, both of whom displayed hematuria.
In 2 brothers with Alport syndrome (ALS1; 301050) without deafness and with relatively late onset, as well as in their carrier mother, Smeets et al. (1992) identified a C-to-G transversion changing a tryptophan codon (TGG) to a serine codon (TCG) in exon 4.
By analysis of genomic DNA from affected members of a kindred with Alport syndrome (ALS1; 301050), Zhou et al. (1992) demonstrated a new HindIII cleavage site. The mutation was found to be located in exon 23: a G-to-T transversion changing the GGT codon of glycine-521 to cysteine (G521C).
In a 6-year-old Italian patient with Alport syndrome (ALS1; 301050), Renieri et al. (1992) demonstrated a de novo mutation resulting in substitution of a glutamic acid for a glycine residue at position 325 (G325E) in the triple helical region of the alpha-5(IV) chain.
Guo et al. (1995) found 2 de novo missense mutations in the COL4A5 gene in a female patient who presented at the age of 19 with microscopic hematuria and nephrotic syndrome. The diagnosis of Alport syndrome (ALS1; 301050) was confirmed by the finding of typical glomerular basement membrane abnormalities on a renal biopsy taken at that age. Renal function deteriorated progressively and chronic hemodialysis was started at the age of 30. A cadaveric kidney transplantation was done 2 years later. There was no hearing loss and there were no clinical features of Turner syndrome. Her height was 162 cm and she had a normal menstrual pattern. Family history showed that her father died at age 36 of renal failure associated with sensorineural hearing loss. An elder sister had microscopic hematuria, proteinuria with normal kidney function, and hearing loss. One mutation (G289V) occurred in exon 15 and converted a glycine in the collagenous domain of COL4A5 to a valine. The second mutation, located in exon 46, substituted a cysteine proximal to the NC1 domain of COL4A5 for an arginine (R1421C). Both mutations were present in more than 90% of the mRNA of white blood cells and kidney, while at the genomic level, the patient was heterozygous for both mutations. The 2 mutations therefore occurred in the same COL4A5 allele. Guo et al. (1995) found no mutations in the COL4A5 promoter region by sequencing, nor did they detect a major rearrangement of the normal allele. A skewed pattern of X inactivation was demonstrated in DNA isolated from the patient's kidney and white blood cells; a normal COL4A5 allele was inactivated in more than 90% of the X chromosomes. The skewed inactivation pattern was thought to be responsible for the absence of detectable normal COL4A5 mRNA and, hence, for the severe phenotype in this woman.
Turco et al. (1995) found a novel missense mutation in exon 3 of the COL4A5 gene in a male patient with late-onset Alport syndrome (ALS1; 301050). Microhematuria was first discovered at age 22 years. He reached end-stage renal disease at age 40, and had a successful transplant at age 41. He had bilateral sensorineural hearing loss and subcapsular posterior lens opacities. The proband had 2 daughters, aged 15 and 13 years. The older daughter had had mild irregular microhematuria since age 2, with normal renal function; a renal biopsy at age 8 showed a thinning of the glomerular basement membrane. In the other daughter, microhematuria was discovered at age 7. Ocular and auditory assessments were normal in both sisters. The proband's mother was known to have microhematuria. The mutation was a G-to-A transition which resulted in a gly54-to-asp (G54D) substitution and abolished a BstNI restriction site. The findings were consistent with the generalization that more slowly progressive forms of Alport syndrome tend to be associated with missense mutations rather than large deletions or frameshifts. The authors stated that this was the first mutation described in the N-terminus triple-helical 7S domain of the COL4A5 gene in an Alport syndrome patient.
Barker et al. (1996) identified a novel leu1649-to-arg (L1649R) mutation in the COL4A5 gene in Alport syndrome (ALS1; 301050) patients. In contrast to most described COL4A5 mutations in Alport syndrome, each of which accounts for the disease in a single family, the L1649R mutation was found in over 7% of the 121 families studied. In males with the L1649R mutation, renal failure preceded hearing loss by approximately 10 years, and the cumulative frequency of hearing loss is 60% by age 60. Barker et al. (1996) noted that substantial variability occurs in the ages at appearance of end-stage renal disease and functional hearing loss among individuals with identical mutations, emphasizing the fallibility of generalizations about the phenotype associated with a specific mutation that is observed in only a small number of Alport syndrome patients.
Nearly all cases of Alport syndrome (ALS1; 301050) involve distinct mutations, as expected for an X-linked disease that significantly reduces the fitness of affected males. A few COL4A5 mutations appear to be associated with reduced disease severity and may account for an appreciable proportion of late-onset Alport syndrome in populations where a founder effect has occurred. Barker et al. (1997) reported a novel mutation in the COL4A5 gene, R1677Q. It was detected in 3 independently ascertained Ashkenazi-American families, caused a relatively mild form of nephritis with typical onset in the fourth or fifth decade, and may be involved in the etiology of a large proportion of adult-onset hereditary nephritis in Ashkenazi Jews. The mutation was a G-to-A transition in nucleotide 5232 and represented a change at a CpG dinucleotide. The same haplotype of COL4A5-linked markers was found in affected males of the 3 kindreds. No genealogic connection could be established.
Ohkubo et al. (2003) found immunohistochemical evidence that the normal anterior lens capsule expressed all of the A4 collagen chains. They also examined the anterior lens capsule of a patient with Alport syndrome due to the R1677X nonsense mutation. The patient's anterior lenticonus resulted in a lack of immunoreactivity to 4A3 to 4A6 chains in the anterior lens capsule.
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