Alternative titles; symbols
HGNC Approved Gene Symbol: COL5A2
SNOMEDCT: 1287094005;
Cytogenetic location: 2q32.2 Genomic coordinates (GRCh38) : 2:189,031,898-189,441,111 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q32.2 | Ehlers-Danlos syndrome, classic type, 2 | 130010 | Autosomal dominant | 3 |
Type V collagen has 3 varieties of alpha chains: alpha-1 (COL5A1, 120215); alpha-2 (COL5A2), and alpha-3 (COL5A3; 120216). It has a specific pericellular distribution and is not considered an interstitial collagen. It is thought also to provide an inner core for large collagen fibers. Thus, collagen V may aid in the orientation of large diameter fibers. (summary by Emanuel et al., 1985).
Burgeson et al. (1976) identified in human fetal membranes (placenta) 2 novel genetically distinct collagen polypeptide chains, which are subunits of a hitherto unknown molecular species of collagen. They were tentatively labeled alpha-A and alpha-B. The existence of a 'new' species of collagen containing one A and two B alpha chains was suggested. This is called collagen V and presumably is determined by 2 loci. Placental collagen is sometimes referred to as AB collagen. Some have considered it to consist of 2 separate molecules, one composed of 3 alpha-A chains and one composed of 3 alpha-B chains. Others view it as a trimer of 1 alpha-A and 2 alpha-B chains. Brown and Weiss (1979) concluded that these are 2 separate molecules (and perhaps a third consisting of 3 alpha-C chains), the first option, and that all 3 chains are derived from one basic chain through posttranslational modification. Type V collagen is usually found between the basement membrane and interstitial space.
Emanuel et al. (1985) concluded that both the alpha-1(III) and the alpha-2(V) procollagen genes map to 2q24.3-q31. To the time of this report, this was the only example of synteny of procollagen genes.
By in situ hybridization and analysis of DNA from somatic cell hybrids, Huerre-Jeanpierre et al. (1986) obtained results consistent with the assignment of COL5A2 to 2q24.3-q31 by Emanuel et al. (1985). Tsipouras et al. (1988) demonstrated that the COL3A1 locus (120180) and the COL5A2 locus are very close together; they found a maximum lod score of 9.33 at a recombination fraction of 0.00.
Hartz (2013) mapped the COL5A2 gene to chromosome 2q32.2 based on an alignment of the COL5A2 sequence (GenBank Y14690) with the genomic sequence (GRCh37).
By microarray analysis, Jun et al. (2001) demonstrated expression of the COL5A2 gene in human donor corneas.
Michalickova et al. (1998) identified mutations in the COL5A2 gene in 2 unrelated patients with Ehlers-Danlos classic type 2 (EDSCL2; 130010) (formerly the severe type I form of EDS). The first proband was heterozygous for a 7-bp deletion that resulted in skipping of exon 27 (120190.0001), whereas the second proband was heterozygous for a single-nucleotide substitution that resulted in skipping of exon 28 (120190.0002). Cultured dermal fibroblasts from both probands produced about equal amounts of the normal and mutant alpha-2(V) mRNAs and protein chains. The dermis from the first proband contained a sparse collagen fibrillar network with great variability in collagen fibril sizes and shapes. The dermal collagens were also abnormally soluble. Bone cells from the first proband also produced about equal amounts of the normal and mutant mRNAs. However, the collagen fibrillar architecture and collagen solubility of the bone matrix were normal. The findings indicated that heterozygous mutations in the COL5A2 gene can produce the classic severe phenotype. Michalickova et al. (1998) suggested that type V collagen plays a more important role in collagen fibrillogenesis of dermis rather than of bone.
Symoens et al. (2012) analyzed COL5A1 (120215) and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations (see EDSCL1, 130000), 13 were COL5A2 mutations, and 7 were COL5A1 null-alleles (see 130000 and 130010) with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra- and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, indicating that this is the major, if not the only, cause of classic EDS.
The tissue-specific organization of collagen molecules into tridimensional macroaggregates determines the physiomechanical properties of most connective tissues. It had been postulated that quantitatively minor types V and XI collagen regulate the growth of type I and type II collagen fibrils, respectively. To test this hypothesis, Andrikopoulos et al. (1995) created mice homozygous for deletion of the Col5a2 gene. These mice survived poorly, possibly because of complications from spinal deformities, and exhibited skin and eye abnormalities caused by disorganized type I collagen fibrils.
Michalickova et al. (1998) screened 28 unrelated individuals and families with typical classic Ehlers-Danlos syndrome for mutations in type V collagen. Of 26 patients in whom no mutations were identified in the COL5A1 gene, they identified abnormalities of COL5A2 cDNA in 2 patients (EDSCL2; 130010). In 1 proband (patient EDS3), the mutation was a 54-bp deletion in heterozygous state (nucleotides 1924-1977 of COL5A2 cDNA). The deletion removed 18 amino acids, gly430 to pro447, from the triple helical domain of the alpha-2(V) chain. The region corresponded to a 54-bp exon, tentatively considered exon 27. This was thought to be due to deletion of the splice acceptor site as a result of a 7-bp deletion that included the consensus ag dinucleotide of the 3-prime splice site of intron 26 and the most 5-prime nucleotides of exon 27.
See 120190.0001. In a patient (patient EDS38) with classic Ehlers-Danlos syndrome (EDSCL2; 130010), Michalickova et al. (1998) found a heterozygous deletion of 54 bp, removing 18 amino acids from the triple helical domain of the alpha-2(V) chain. In this case, however, nucleotides 1978 to 2031 were removed. It was thought that the mutation had resulted in deletion of exon 28. The patient was found to be heterozygous for a single nucleotide substitution that changed the consensus gt dinucleotide of the 5-prime splice donor of intron 28 to tt. They concluded from the nature of the mutation that the missing splice donor site caused exon 28 to be skipped during splicing of the mutant allele of COL5A2. Studies in the parents indicated that this was a new mutation.
In 3 family members with classic Ehlers-Danlos syndrome (EDSCL2; 130010), Richards et al. (1998) found a G-C base change in the COL5A2 gene, resulting in the substitution of arginine for glycine within the triple helical domain at position 934.
In a patient (patient EDS2) with classic Ehlers-Danlos syndrome (EDSCL2; 130010), Malfait et al. (2005) identified a splice site mutation (c.2544+2delT, NM_000393.2) in the COL5A2 gene, predicted to result in the skipping of exon 36.
In a patient (patient EDS2) with classic Ehlers-Danlos syndrome (EDSCL2; 130010), Malfait et al. (2005) identified a 1-bp deletion (c.4289delT) in the COL5A2 gene, predicted to result in a frameshift and a premature termination codon (c.4289delT, NM_000393.2).
In a patient (patient EDS6) with classic Ehlers-Danlos syndrome (EDSCL2; 130010), Malfait et al. (2005) identified a splice site mutation (c.3139-2A-G, NM_000393.2) in the COL5A2 gene, predicted to result in deletion of exon 43.
In a patient (patient EDS22) with classic Ehlers-Danlos syndrome (EDSCL2; 130010), Malfait et al. (2005) identified a splice site mutation (c.1608+4T-C, NM_000393.2) in the COL5A2 gene, predicted to result in deletion of exon 22.
Andrikopoulos, K., Liu, X., Keene, D. R., Jaenisch, R., Ramirez, F. Targeted mutation in the col5a2 gene reveals a regulatory role for type V collagen during matrix assembly. Nature Genet. 9: 31-36, 1995. [PubMed: 7704020] [Full Text: https://doi.org/10.1038/ng0195-31]
Brown, R. A., Weiss, J. B. Type V collagen: possible shared identity of alpha-A, alpha-B and alpha-C chains. FEBS Lett. 106: 71-75, 1979. [PubMed: 499505] [Full Text: https://doi.org/10.1016/0014-5793(79)80697-3]
Burgeson, R. E., El Adli, F. A., Kaitila, I. J., Hollister, D. W. Fetal membrane collagens: identification of two new collagen alpha chains. Proc. Nat. Acad. Sci. 73: 2579-2583, 1976. [PubMed: 1066666] [Full Text: https://doi.org/10.1073/pnas.73.8.2579]
Emanuel, B. S., Cannizzaro, L. A., Seyer, J. M., Myers, J. C. Human alpha-1(III) and alpha-2(V) procollagen genes are located on the long arm of chromosome 2. Proc. Nat. Acad. Sci. 82: 3385-3389, 1985. [PubMed: 3858826] [Full Text: https://doi.org/10.1073/pnas.82.10.3385]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/28/2013.
Huerre-Jeanpierre, C., Henry, I., Bernard, M., Gallano, P., Weil, D., Grzeschik, K.-H., Ramirez, F., Junien, C. The pro-alpha-2(V) collagen gene (COL5A2) maps to 2q14-2q32, syntenic to the pro-alpha-1(III) collagen locus (COL3A1). Hum. Genet. 73: 64-67, 1986. [PubMed: 3011647] [Full Text: https://doi.org/10.1007/BF00292666]
Jun, A. S., Liu, S. H., Koo, E. H., Do, D. V., Stark, W. J., Gottsch, J. D. Microarray analysis of gene expression in human donor corneas. Arch. Ophthal. 119: 1629-1634, 2001. [PubMed: 11709013] [Full Text: https://doi.org/10.1001/archopht.119.11.1629]
Malfait, F., Coucke, P., Symoens, S., Loeys, B., Nuytinck, L., De Paepe, A. The molecular basis of classic Ehlers-Danlos syndrome: a comprehensive study of biochemical and molecular findings in 48 unrelated patients. Hum. Mutat. 25: 28-37, 2005. [PubMed: 15580559] [Full Text: https://doi.org/10.1002/humu.20107]
Michalickova, K., Susic, M., Willing, M. C., Wenstrup, R. J., Cole, W. G. Mutations of the alpha-2(V) chain of type V collagen impair matrix assembly and produce Ehlers-Danlos syndrome type I. Hum. Molec. Genet. 7: 249-255, 1998. [PubMed: 9425231] [Full Text: https://doi.org/10.1093/hmg/7.2.249]
Richards, A. J., Martin, S., Nicholls, A. C., Harrison, J. B., Pope, F. M., Burrows, N. P. A single base mutation in COL5A2 causes Ehlers-Danlos syndrome type II. J. Med. Genet. 35: 846-848, 1998. [PubMed: 9783710] [Full Text: https://doi.org/10.1136/jmg.35.10.846]
Sage, H., Bornstein, P. Characterization of a novel collagen chain in human placenta and its relation to AB collagen. Biochemistry 18: 3815-3822, 1979. [PubMed: 224919] [Full Text: https://doi.org/10.1021/bi00584a027]
Symoens, S., Syx, D., Malfait, F., Callewaert, B., De Backer, J., Vanakker, O., Coucke, P., De Paepe, A. Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Hum. Mutat. 33: 1485-1493, 2012. [PubMed: 22696272] [Full Text: https://doi.org/10.1002/humu.22137]
Tsipouras, P., Schwartz, R. C., Liddell, A. C., Salkeld, C. S., Weil, D., Ramirez, F. Genetic distance of two fibrillar collagen loci, COL3A1 and COL5A2, located on the long arm of human chromosome 2. Genomics 3: 275-277, 1988. [PubMed: 3224983] [Full Text: https://doi.org/10.1016/0888-7543(88)90089-4]
van der Rest, M., Niyibizi, C., Fietzek, P. P. Human placental alpha-1(V)alpha-2(V)alpha-3(V) and [alpha-1(V)]-2-alpha-2(V) collagen heterotrimers. Ann. N.Y. Acad. Sci. 460: 517-519, 1985.