Alternative titles; symbols
HGNC Approved Gene Symbol: COL6A5
Cytogenetic location: 3q22.1 Genomic coordinates (GRCh38): 3:130,345,672-130,484,846 (from NCBI)
COL6A5, or COL29A1, belongs to the class of collagens containing von Willebrand factor (VWF; 613160) type A (VWA) domains. These collagens form filaments with globular domains containing VWA motifs, which are involved in protein-ligand interactions for the organization of tissue architecture and cell adhesion (Soderhall et al., 2007).
By positional cloning in the chromosome 3q21 candidate susceptibility region for atopic dermatitis (ATOD1; 603165), Soderhall et al. (2007) cloned COL29A1. The deduced 2,614-amino acid protein has a calculated molecular mass of 289.9 kD and shares 32% amino acid identity with COL6A3 (120250). COL29A contains 6 N-terminal and 3 C-terminal VWA domains flanking a short collagen triple helix, and an 18-amino acid secretion signal. Northern blot analysis detected a 9.6-kb transcript in human skin. RT-PCR analysis detected highest expression in skin, followed by lung, small intestine, colon, and testis.
Gara et al. (2008) cloned mouse Col6a5. The deduced 2,658-amino acid protein has an N-terminal signal peptide, followed by 7 VWA domains, a collagen triple-helical domain, 3 additional VWA domains, and a unique C-terminal end. The mature secreted protein has a calculated molecular mass of 287.5 kD. Gara et al. (2008) cloned the human COL6A5 gene by RT-PCR of HT1080 or HEK293-EBNA cells. Database analysis revealed alternative splicing resulting in 4 different C termini in human proteins containing 2,526, 2,590, 2,614, or 2,615 amino acids. The longest human isoform shares 73.1% amino acid identity with mouse Col6a5. Northern blot analysis detected a 9.5-kb Col6a5 transcript in 4-week-old mouse sternum. RT-PCR detected variable expression of Col6a5 in all 10 mouse tissues examined except calvaria. Immunohistochemical analysis detected Col6a5 in skeletal muscle of adult mice.
Soderhall et al. (2007) determined that the COL6A5 gene contains 42 exons spanning 139 kb.
By positional cloning and genomic sequence analysis, Soderhall et al. (2007) mapped the COL6A5 gene to chromosome 3q21.
Gara et al. (2008) mapped the mouse Col6a5 gene to a region of chromosome 9F1 that shares homology of synteny with human chromosome 3q21.
By immunohistochemical analysis, Gara et al. (2008) detected expression of Col6a5 and Col6a6 (616613) in quadriceps femoris and diaphragm of wildtype mice, but not in Col6a1 (120220)-deficient mice, suggesting that the alpha-1 chain is a prerequisite for trimeric assembly of collagens containing Col6a5 and Col6a6.
Soderhall et al. (2007) analyzed the candidate COL29A1 gene in 46 unrelated children with atopic dermatitis and 2 controls and identified 13 common and 6 rare sequence variations causing nonsynonymous amino acid substitutions. All coding SNPs were genotyped in 199 ATOD families originally studied by Lee et al. (2000); 4 SNPs showed a positive association with ATOD, but that association did not account for the previously observed haplotype association. In situ hybridization and immunohistochemical analysis of normal human skin detected COL29A1 expression in the epidermis with strongest staining in suprabasal viable layers. However, in situ hybridization of the skin of patients with ATOD demonstrated an absence of COL29A1 expression in the most differentiated upper spinous and granular layers, although overall COL29A1 expression levels remained the same between patients and controls. Soderhall et al. (2007) concluded that ATOD patients displayed an abnormal distribution of COL29A1 mRNA and protein in skin and suggested that COL29A1 is involved in the pathogenesis of ATOD.
Associations Pending Confirmation
In affected members of 3 unrelated families with autosomal dominant transmission of chronic neuropathic itch, Martinelli-Boneschi et al. (2017) identified 2 heterozygous variants in the COL6A5 gene. Five patients from families 1 and 2 carried a heterozygous nonsense polymorphism (E2272X; 611916.0001), whereas all 3 affected individuals from family 3 carried a heterozygous missense variant (c.6486G-C, Arg2162Ser, R2162S, rs368345789). The variants, which were found by whole-exome sequencing, segregated with the disorder in all families, but both were present at low frequencies in the ExAC and gnomAD databases (0.007 for E2272X and 2.5 x 10(-5) for R2162S). Family 3 had previously been reported by Devigili et al. (2014) as having a heterozygous missense variant in the SCN9A gene (I739V; 603415.0027), which had been thought to be responsible for the phenotype (see 133020). Functional studies of the R2162S variant were not performed. The phenotype was similar in the patients from all 3 families, although the age at onset ranged from childhood to adulthood. Itch involved the trunk and upper limbs with daily episodes of fluctuating intensity. The patients in families 1 and 2 could not identified a trigger for the itch, whereas the patients in family 3, with the SCN9A mutation, reported triggering by environmental warmth. Atopic dermatitis and other systemic conditions were ruled out in all patients. Skin biopsies in members from all 3 families showed reduced intraepidermal nerve fiber densities in most, but not all, patients. Treatment with gabapentin was effective in all families.
In 5 patients from 2 unrelated families (families 1 and 2) with autosomal dominant transmission of chronic neuropathic itch, Martinelli-Boneschi et al. (2017) identified a heterozygous c.6814G-T transversion in the COL6A5 gene, resulting in a glu2272-to-ter (E2272X) substitution. The variant, which was found by whole-exome sequencing, segregated with the disorder in both families. Western blot analysis of patient fibroblasts showed about 50% of the wildtype protein compared to controls, suggesting that the mutation results in nonsense-mediated mRNA decay and functional haploinsufficiency. COL6A5 expression was also reduced in the papillary dermis and around the dermal vessels of patients compared to controls.
Martinelli-Boneschi et al. (2017) noted that the E2272X variant had a low frequency (0.0096) in the ExAC database. Hamosh (2020) found that the E2272X variant had a frequency of 0.007 in the gnomAD database, present in 1,927 of 273,850 alleles, with 16 homozygotes, suggesting that it is a polymorphism (May 26, 2020).
Devigili, G., Eleopra, R., Pierro, T., Lombardi, R., Rinaldo, S., Lettieri, C., Faber, C. G., Merkies, I. S. J., Waxman, S. G., Lauria, G. Paroxysmal itch caused by gain-of-function Na(v)1.7 mutation. Pain 155: 1702-1707, 2014. [PubMed: 24820863] [Full Text: https://doi.org/10.1016/j.pain.2014.05.006]
Gara, S. K., Grumati, P., Urciuolo, A., Bonaldo, P., Kobbe, B., Koch, M., Paulsson, M., Wagener, R. Three novel collagen VI chains with high homology to the alpha-3 chain. J. Biol. Chem. 283: 10658-10670, 2008. [PubMed: 18276594] [Full Text: https://doi.org/10.1074/jbc.M709540200]
Hamosh, A. Personal Communication. Baltimore, Md. 05/26/2020.
Lee, Y.-A., Wahn, U., Kehrt, R., Tarani, L., Businco, L., Gustafsson, D., Andersson, F., Oranje, A. P., Wolkertstorfer, A., v. Berg, A., Hoffmann, U., Kuster, W., Wienker, T., Ruschendorf, F., Reis, A. A major susceptibility locus for atopic dermatitis maps to chromosome 3q21. Nature Genet. 26: 470-473, 2000. [PubMed: 11101848] [Full Text: https://doi.org/10.1038/82625]
Martinelli-Boneschi, F., Colombi, M., Castori, M., Devigili, G., Eleopra, R., Malik, R. A., Ritelli, M., Zoppi, N., Dordoni, C., Sorosina, M., Grammatico, P., Fadavi, H., and 17 others. COL6A5 variants in familial neuropathic chronic itch. Brain 140: 555-567, 2017. [PubMed: 28073787] [Full Text: https://doi.org/10.1093/brain/aww343]
Soderhall, C., Marenholz, I., Kerscher, T., Ruschendorf, F., Esparza-Gordillo, J., Worm, M., Gruber, C., Mayr, G., Albrecht, M., Rohde, K., Schulz, H., Wahn, U., Hubner, N., Lee, Y.-A. Variants in a novel epidermal collagen gene (COL29A1) are associated with atopic dermatitis. PLoS Biol. 5: e242, 2007. Note: Electronic Article. [PubMed: 17850181] [Full Text: https://doi.org/10.1371/journal.pbio.0050242]