Alternative titles; symbols
HGNC Approved Gene Symbol: COL4A4
SNOMEDCT: 236418003;
Cytogenetic location: 2q36.3 Genomic coordinates (GRCh38): 2:226,967,360-227,164,488 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q36.3 | Alport syndrome 2, autosomal recessive | 203780 | Autosomal recessive | 3 |
| Hematuria, familial benign, 1 | 141200 | Autosomal dominant | 3 |
Type IV collagen is found only in basement membranes, where it is the major structural component. COL4A4 is 1 of 6 alpha chains that form the heterotrimeric type IV collagen molecules (Mariyama et al., 1994).
Butkowski et al. (1987) and Saus et al. (1988) identified 2 type IV collagen alpha chains distinct from the alpha-1 (COL1A1; 120130) and alpha-2 (120090) chains. These are designated alpha-3 (120070) and alpha-4. Gunwar et al. (1990) characterized further the alpha-4 chain of type IV collagen.
Mariyama et al. (1992) isolated partial cDNAs for the COL4A4 gene. On the basis of comparisons of the deduced peptide sequences of all 5 chains of type IV collagen, Mariyama et al. (1992) concluded that they can be divided into 2 families: those that resemble alpha-1 (COL4A1, COL4A3, and COL4A5), and those that resemble alpha-2 (COL4A2 and COL4A4). The COL4A1 and COL4A2 chains are commonly found together in basement membrane and form heterotrimers. Whereas alpha-1(IV) and alpha-2(IV) are found in all basement membranes studied, alpha-3(IV) and alpha-4(IV) are found only in a subset of basement membranes. They are always found together, however.
Leinonen et al. (1994) determined the entire sequence of the COL4A4 gene. The complete translation product has 1,690 amino acid residues and the processed polypeptide contains 1,652 residues. There is a 38-residue putative signal peptide, a 1,421-residue collagenous domain starting with a 23-residue noncollagenous sequence, and a 231-residue NC1 domain. Differences and similarities with the other component chains of type IV collagen were detailed.
Using Northern blot analysis, Mariyama et al. (1994) found high expression of a 10-kb COL4A44 transcript in adult human kidney, skeletal muscle, and lung and in fetal kidney and lung. A 7.5-kb transcript was also detected in fetal kidney and lung, with weaker expression in fetal heart. Expression of COL4A4 largely overlapped that of COL4A3, suggesting that expression of the 2 transcripts may be coregulated.
Momota et al. (1998) identified 2 alternative first exons, exons 1 and 1-prime, used by COL4A4 transcripts. Both exons are noncoding. Southern blot analysis of 5-prime RACE products amplified from human tissues and cell lines showed that exon 1 was expressed predominantly in epithelial cells, while exon 1-prime was ubiquitously expressed at lower levels.
Using cDNA probes generated from normal dog kidney, Thorner et al. (1996) compared the nucleotide and deduced amino acid sequences of normal canine and human alpha-1 type IV collagen to the alpha-4 type IV and alpha-6 type IV (303631) chains. They found that the canine sequences are over 88% identical at the DNA level and over 92% identical at the protein level to the respective human alpha chains. The positions of the cysteine residues are conserved between all canine alpha type IV chains and between each canine and human alpha IV chain.
Momota et al. (1998) determined that the COL4A4 gene contains alternative noncoding first exons, designated exons 1 and 1-prime. Exon 2 contains the translation start site. The COL4A3 and COL4A4 genes are on opposite strands of chromosome 2 and are transcribed in opposite directions. The first exon of COL4A3 is separated from exons 1 and 1-prime 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.
Boye et al. (1998) determined that the COL4A4 gene contains 48 exons.
By analysis of somatic cell hybrids and by in situ hybridization, Mariyama et al. (1992) mapped the COL4A3 and COL4A4 genes to the same region, 2q35-q37.
Mariyama et al. (1992) stated that COL4A1 and COL4A2 map to 13q34 and are transcribed from opposite DNA strands using a common bidirectional promoter that allows coordinate regulation of the 2 chains. The COL4A3 and COL4A4 genes are arranged in a head-to-head manner on 2q.
Kamagata et al. (1992) compared the COL4A4 chain with the other 4 chains of type IV collagen. Using a human genomic DNA fragment for in situ hybridization, they mapped the COL4A4 gene to 2q35-q37.1.
Of 7 families with presumed autosomal recessive Alport syndrome (ATS2; 203780), Mochizuki et al. (1994) demonstrated COL4A4 mutations in 2 (120131.0001-120131.0002).
Lemmink et al. (1997) reviewed the clinical spectrum associated with mutations of the several chains of type IV collagen. They listed the 3 mutations that had been identified in the COL4A4 gene: 1 in familial benign hematuria (120131.0003) and 2 in Alport syndrome with development of renal failure at 14 and 18 years of age, respectively.
Boye et al. (1998) characterized the 48 exons of the COL4A4 gene and detected 10 novel mutations in 8 patients diagnosed with autosomal recessive Alport syndrome (see, e.g., 120131.0004-120131.0006). Furthermore, they identified a glycine-to-alanine substitution in the collagenous domain that is apparently silent in heterozygous carriers, in 11.5% of all control individuals, and in 1 control individual homozygous for this glycine substitution. There had been no previous finding of a glycine substitution that was not associated with any obvious phenotype in homozygous individuals.
In affected members of 4 unrelated families with benign familial hematuria, Badenas et al. (2002) identified 4 different heterozygous mutations in the COL4A4 gene (see, e.g., 120131.0007 and 120131.0008).
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 (120070) and COL4A4, 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.
Associations Pending Confirmation
For discussion of a possible association between variation in the COL4A4 gene and keratoconus, see KTCN1 (148300).
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 (303630) 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, 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 to 23% and 11 to 17%, respectively. These findings suggested to Thorner et al. (1996) a mechanism that coordinates the expression of these 3 basement membrane proteins.
See 120070 for the description of a mouse model of human Alport syndrome.
In 2 Algerian sisters (family BE) with autosomal recessive Alport syndrome (ATS2; 203780), Mochizuki et al. (1994) identified homozygosity for a G-to-A transition in a portion of the COL4A4 gene representing a segment of the 3-prime third of the alpha-4(IV) collagenous domain. The mutation resulted in a substitution of a serine residue for a glycine residue that is part of the Gly-X-Y collagenous repeat. The authors considered the variant pathogenic for several reasons. The asymptomatic consanguineous parents and an unaffected brother were heterozygous for the variant. The mutant allele was not observed in 32 unrelated persons from the same North African population. Similar glycine-to-serine substitutions had been observed in the fibrillar collagens encoded by the COL1A1 and COL1A2 genes in osteogenesis imperfecta. Moreover, a serine-for-glycine substitution had been observed in the alpha-5(IV) chain in a patient with X-linked Alport syndrome (301050). The authors noted that the glycine-to-serine mutations in both the COL4A4 and COL4A5 genes are recessive, whereas similar mutations in fibrillar collagens are dominant. In the Algerian family, end-stage renal disease developed in the older sister at the age of 14, but no deafness or ocular abnormalities had been observed. The other sister was noted at age 11 to have the nephrotic syndrome without a decrease in renal function; likewise, no deafness or ocular abnormalities were found.
In a review of mutations in the type IV collagen genes, Lemmink et al. (1997) stated that this mutation was a G-to-A transition at nucleotide 3809, resulting in a gly1201-to-ser (G1201S) amino acid substitution.
In an Italian girl (family GA) with autosomal recessive Alport syndrome (ATS2; 203780), Mochizuki et al. (1994) observed a homozygous substitution of A for C in the collagenous domain of alpha-4(IV). The mutation replaced a serine codon with a stop codon, causing premature chain termination and shortening of the chain by 453 amino acids. The parents were not known to be consanguineous but shared the same surname and originated from the same village in Italy. Two of the proband's sisters had died at ages 8 and 12 years, apparently of Alport syndrome.
In a review of mutations in the type IV collagen genes, Lemmink et al. (1997) indicated that this homozygous mutation was a C-to-A transversion at nucleotide 3921, resulting in a ser1238-to-ter (S1238X) nonsense mutation. Renal failure occurred at age 18 years.
Benign familial hematuria (BFH1; 141200) is characterized by autosomal dominant inheritance, thinning of the glomerular basement membrane (GBM), and normal renal function. It is frequent in patients with persistent microscopic hematuria, but cannot be clinically differentiated from the initial stages of Alport syndrome (see 203780), a severe GBM disorder which progresses to renal failure. Lemmink et al. (1996) demonstrated linkage of BFH with the COL4A3 and COL4A4 genes at 2q35-q37 and went on to demonstrate a GGG-to-GAG transition in codon 897 of COL4A4 resulting in substitution of a glutamic acid residue for glycine. The G-to-A mutation in this family introduced a novel site for the restriction enzyme AluI, by which the members of the family were screened. All affected members of the family in 3 generations were heterozygous. The index patient, a member of the third generation, presented with hematuria at the age of 5 years. Family history was negative for renal failure and deafness. Electron microscopy of a renal biopsy specimen showed regions with malformations of the GBM typical for Alport syndrome and regions that were thin. Microscopic hematuria was present in many relatives, including the 75-year-old paternal grandfather who had a normal serum creatinine concentration. The family was complicated by the fact that the mother of the index case also had microscopic hematuria as did many of her relatives. She did not carry the gly897-to-glu mutation nor was another mutation identified. The index patient, 16 years old at the time of the report, had developed proteinuria and may have inherited a COL4A4 gene mutation from both parents. Lemmink et al. (1996) speculated that this might account for the histologic changes in the GBM suggesting Alport syndrome. Homozygous mutations in COL4A3 and COL4A4 have been identified in autosomal recessive Alport syndrome.
In a family with autosomal recessive Alport syndrome (ALS2; 203780), Boye et al. (1998) found that affected individuals were compound heterozygotes for 2 mutations in the COL4A4 gene: a C-to-T transition at nucleotide 4337 in exon 44, resulting in an arg1377-to-ter (R1377X) nonsense mutation; and a C-to-A transversion at nucleotide 5131 resulting in a cys1641-to-ter (C1641X; 120131.0005) nonsense mutation.
For discussion of the 513C-A transversion in the COL4A4 gene, resulting in a cys164-to-ter (C164X) substitution, that was found in compound heterozygous state in affected members of a family with autosomal recessive Alport syndrome (ATS2; 203780) by Boye et al. (1998), see 120131.0004.
Boye et al. (1998) found that one of the alleles of the COL4A4 gene in a patient with autosomal recessive Alport syndrome (ATS2; 203780) carried a C-to-T transition at nucleotide 4923 in exon 47, resulting in a pro1572-to-leu (P1572L) substitution. The change was not found in any of 48 control individuals.
In affected members of a family (HFB-7) with benign familial hematuria (BFH1; 141200), Badenas et al. (2002) identified a heterozygous 1-bp insertion (3222insA) in exon 35 of the COL4A4 gene, predicted to result in a frameshift and premature termination.
In affected members of a family (HFB-9) with benign familial hematuria (BFH1; 141200), Badenas et al. (2002) identified a heterozygous mutation in exon 32 of the COL4A4 gene, resulting in a gly960-to-arg (G960R) substitution. The mutation was not found in 200 control chromosomes.
Badenas, C., Praga, M., Tazon, B., Heidet, L., Arrondel, C., Armengol, A., Andres, A., Morales. E., Camacho, J. A., Lens, X., Davila, S., Mila, M., Antignac, C., Darnell, A., Torra, R. Mutations in the COL4A4 and COL4A3 genes cause familial benign hematuria. J. Am. Soc. Nephrol. 13: 1248-1254, 2002. [PubMed: 11961012] [Full Text: https://doi.org/10.1681/ASN.V1351248]
Boye, E., Mollet, G., Forestier, L., Cohen-Solal, L., Heidet, L., Cochat, P., Grunfeld, J.-P., Palcoux, J.-B., Gubler, M.-C., Antignac, C. Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am. J. Hum. Genet. 63: 1329-1340, 1998. [PubMed: 9792860] [Full Text: https://doi.org/10.1086/302106]
Butkowski, R. J., Langeveld, J. P. M., Wieslander, J., Hamilton, J., Hudson, B. G. Localization of the Goodpasture epitope to a novel chain of basement membrane collagen. J. Biol. Chem. 262: 7874-7877, 1987. [PubMed: 2438283]
Gunwar, S., Saus, J., Noelken, M. E., Hudson, B. G. Glomerular basement membrane: identification of a fourth chain, alpha-4, of type IV collagen. J. Biol. Chem. 265: 5466-5469, 1990. [PubMed: 2318822]
Kamagata, Y., Mattei, M.-G., Ninomiya, Y. Isolation and sequencing of cDNAs and genomic DNAs encoding the alpha 4 chain of basement membrane collagen type IV and assignment of the gene to the distal long arm of human chromosome 2. J. Biol. Chem. 267: 23753-23758, 1992. [PubMed: 1429714]
Leinonen, A., Mariyama, M., Mochizuki, T., Tryggvason, K., Reeders, S. T. Complete primary structure of the human type IV collagen alpha-4(IV) chain: comparison with structure and expression of the other alpha(IV) chains. J. Biol. Chem. 269: 26172-26177, 1994. [PubMed: 7523402]
Lemmink, H. H., Nillesen, W. N., Mochizuki, T., Schroder, C. H., Brunner, H. G., van Oost, B. A., Monnens, L. A. H., Smeets, H. J. M. Benign familial hematuria due to mutation of the type IV collagen alpha-4 gene. J. Clin. Invest. 98: 1114-1118, 1996. [PubMed: 8787673] [Full Text: https://doi.org/10.1172/JCI118893]
Lemmink, H. H., Schroder, C. H., Monnens, L. A. H., Smeets, H. J. M. The clinical spectrum of type IV collagen mutations. Hum. Mutat. 9: 477-499, 1997. [PubMed: 9195222] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)9:6<477::AID-HUMU1>3.0.CO;2-#]
Mariyama, M., Leinonen, A., Mochizuki, T., Tryggvason, K., Reeders, S. T. Complete primary structure of the human alpha-3(IV) collagen chain: coexpression of the alpha-3(IV) and alpha-4(IV) collagen chains in human tissues. J. Biol. Chem. 269: 23013-23017, 1994. [PubMed: 8083201]
Mariyama, M., Zheng, K., Yang-Feng, T. L., Reeders, S. T. Colocalization of the genes for the alpha-3(IV) and alpha-4(IV) chains of type IV collagen to chromosome 2 bands q35-q37. Genomics 13: 809-813, 1992. [PubMed: 1639407] [Full Text: https://doi.org/10.1016/0888-7543(92)90157-n]
Mencarelli, M. A., Heidet, L., Storey, H., van Geel, M., Knebelmann, B., Fallerini, C., Miglietti, N., Antonucci, M. F., Cetta, F., Sayer, J. A., van den Wijngaard, A., Yau, S., Mari, F., Bruttini, M., Ariani, F., Dahan, K., Smeets, B., Antignac, C., Flinter, F., Renieri, A. Evidence of digenic inheritance in Alport syndrome. J. Med. Genet. 52: 163-174, 2015. [PubMed: 25575550] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102822]
Mochizuki, T., Lemmink, H. H., Mariyama, M., Antignac, C., Gubler, M.-C., Pirson, Y., Verellen-Dumoulin, C., Chan, B., Schroder, C. H., Smeets, H. J., Reeders, S. T. Identification of mutations in the alpha-3(IV) and alpha-4(IV) collagen genes in autosomal recessive Alport syndrome. Nature Genet. 8: 77-81, 1994. [PubMed: 7987396] [Full Text: https://doi.org/10.1038/ng0994-77]
Momota, R., Sugimoto, M., Oohashi, T., Kigasawa, K., Yoshioka, H., Ninomiya, Y. Two genes, COL4A3 and COL4A4 coding for the human alpha-3(IV) and alpha-4(IV) collagen chains are arranged head-to-head on chromosome 2q36. FEBS Lett. 424: 11-16, 1998. [PubMed: 9537506] [Full Text: https://doi.org/10.1016/s0014-5793(98)00128-8]
Saus, J., Wieslander, J., Langeveld, J. P. M., Quinones, S., Hudson, B. G. Identification of the Goodpasture antigen as the alpha-3(IV) chain of collagen IV. J. Biol. Chem. 263: 13374-13380, 1988. [PubMed: 3417661]
Thorner, P. S., Zheng, K., Kalluri, R., Jacobs, R., Hudson, B. G. Coordinate gene expression of the alpha-3, alpha-4, and alpha-5 chains if collagen type IV. J. Biol. Chem. 271: 13821-13828, 1996. [PubMed: 8662866] [Full Text: https://doi.org/10.1074/jbc.271.23.13821]