HGNC Approved Gene Symbol: COL8A2
Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38): 1:36,095,239-36,125,222 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.3 | Corneal dystrophy, Fuchs endothelial, 1 | 136800 | Autosomal dominant | 3 |
| Corneal dystrophy, posterior polymorphous 2 | 609140 | Autosomal dominant | 3 |
Type VIII collagen molecules, expressed by corneal and vascular endothelial cells, are heterotrimers composed of 2 genetically distinct polypeptides, alpha-1(VIII) (COL8A1; 120251) and alpha-2(VIII) (COL8A2; 120252), in the ratio of 2:1. Collagen VIII is a member of the 'short chain collagen' subfamily. It is a major component of the hexagonal lattice in the Descemet membrane (Muragaki et al., 1991).
Muragaki et al. (1991) characterized the COL8A2 gene, which encodes a deduced 644-amino acid protein with 3 domains. The N-terminal region consists of 20 residues of non-triple-helical sequence (NC2), followed by a triple-helical sequence of 457 residues. The triple-helical domain (COL1) is contiguous with a 167-residue non-triple helical domain (NC1) on the carboxyl side.
The triple-helical and carboxyl non-triple-helical domains of COL8A1 are encoded by a single, large exon in both mice and humans (Muragaki et al., 1991).
By in situ hybridization, Muragaki et al. (1991) demonstrated that the COL8A2 gene is located in the region 1p34.3-p32.3.
Corneal endothelial dystrophies arise from dysfunction of the corneal epithelium, leading to corneal opacification. Biswas et al. (2001) conducted a genomewide search of a 3-generation family with early-onset Fuchs endothelial corneal dystrophy (FECD1; 136800) and identified a critical region of 6 to 7 cM at chromosome 1p34.3-p32, which includes the COL8A2 gene. Analysis of its coding sequence identified a gln455-to-lys missense mutation (120252.0001) within the triple helical domain of the protein in this family. Mutation analysis in other patients demonstrated additional missense substitutions in familial and sporadic cases of FECD, as well as in a single family with polymorphous posterior corneal dystrophy (PPCD2; 609140). The authors suggested that the underlying pathogenesis of FECD and PPCD2 may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest-derived corneal endothelial cell.
In affected members of the autosomal dominant kindred with early-onset Fuchs corneal dystrophy reported by Magovern et al. (1979), Gottsch et al. (2005) identified heterozygosity for a novel point mutation in the COL8A2 gene that resulted in an L450W amino acid substitution (120252.0003).
In a 3-generation family with late-onset FECD, Biswas et al. (2001) identified heterozygosity for a G-to-A transition that resulted in an arg155-to-gln (R155Q) mutation. However, among 15 unrelated Japanese patients with late-onset FECD, Kobayashi et al. (2004) found heterozygosity for the R155Q mutation not only in 3 patients but also in 5 of 72 chromosomes (6.9%) from normal subjects. Moreover, investigation of family members of a proband with the R155Q mutation revealed that the 87-year-old mother carried the R155Q mutation in homozygosity (and another mutation in heterozygosity) but showed no corneal guttae or endothelial cell decrease. Kobayashi et al. (2004) concluded that the R155Q mutation in the COL8A2 gene may not be causative for the disorder.
In affected members of a 3-generation British family with Fuchs endothelial corneal dystrophy, Liskova et al. (2007) identified heterozygosity for the L450W mutation in the COL8A2 gene.
Mok et al. (2009) screened the COL8A2 gene in 25 Korean FECD patients, including 15 patients from 6 pedigrees with early-onset disease and 10 unrelated patients, and identified heterozygosity for a missense mutation (Q455V; 120252.0004) in all familial FECD patients as well as in 2 of the sporadic cases.
Jun et al. (2012) studied homozygous knockin 10-month-old mice carrying the Col8a2 Q455K mutation (120252.0001) and observed features strikingly similar to human disease, including progressive alterations in endothelial cell morphology, cell loss, and basement membrane guttae. Ultrastructural analysis showed the predominant effect to be dilated endoplasmic reticulum (ER), suggesting ER stress and unfolded protein response (UPR) activation. Immunohistochemistry, Western blot, QT-PCR, and TUNEL analyses supported UPR activation and UPR-associated apoptosis in the mutant corneal endothelium. Jun et al. (2012) concluded that the Q455K mutation in COL8A2 causes FECD through a mechanism involving the UPR and UPR-associated apoptosis.
Meng et al. (2013) generated knockin mice homozygous for the Col8a2 L450W mutation (120252.0003) and observed a milder corneal endothelial phenotype than that of the homozygous Q455K mice reported by Jun et al. (2012); however, both mutants exhibited the hallmarks of FECD, including reduced numbers of endothelial cells, presence of guttae, and variations in cell size as well as deviations from the normal hexagonal shape. In addition, both mutants showed upregulation of the UPR as evidenced by dilated rough ER and upregulation of UPR-associated genes and proteins. RT-PCR of corneal endothelial cells from L450W and Q455K mutant mice at 40 weeks revealed 2.1- and 5.2-fold upregulation of the autophagy marker Dram1 (610776), respectively. RT-PCR of human FECD endothelium of unknown genotype showed 10.4-fold upregulation of DRAM1 compared to autopsy controls. Meng et al. (2013) suggested that altered autophagy plays a role in FECD.
In all 13 affected individuals tested within a 3-generation family with early-onset Fuchs endothelial corneal dystrophy (FECD1; 136800), Biswas et al. (2001) demonstrated heterozygosity for a c.1364C-A transversion in the COL8A2 gene that resulted in a gln455-to-lys (Q455K) mutation. The identical mutation was found in 2 individuals from another family with ultrastructural changes consistent with posterior polymorphous corneal dystrophy (PPCD2; 609140).
Jun et al. (2012) studied homozygous knockin 10-month-old mice carrying the Col8a2 Q455K mutation and observed features strikingly similar to human disease, including progressive alterations in endothelial cell morphology, cell loss, and basement membrane guttae. Ultrastructural analysis showed the predominant effect to be dilated endoplasmic reticulum (ER), suggesting ER stress and unfolded protein response (UPR) activation. Immunohistochemistry, Western blot, QT-PCR, and TUNEL analyses supported UPR activation and UPR-associated apoptosis in the mutant corneal endothelium.
In the autosomal dominant kindred with early-onset Fuchs endothelial corneal dystrophy (FECD1; 136800) reported by Magovern et al. (1979), Gottsch et al. (2005) found that affected members were heterozygous for a T-to-G transversion in the COL8A2 gene that resulted in a leu450-to-trp (L450W) substitution in the collagen repeat domain of the protein. The mutation was also found in 1 member with posterior polymorphous corneal dystrophy (PPCD2; 609140).
In affected members of a 3-generation British family with FECD, Liskova et al. (2007) identified heterozygosity for the L450W mutation in the COL8A2 gene.
Meng et al. (2013) generated knockin mice homozygous for the Col8a2 L450W mutation and observed the hallmarks of FECD, including reduced numbers of endothelial cells, presence of guttae, and variations in cell size with deviations from the normal hexagonal shape. In addition, there was upregulation of the UPR as evidenced by dilated rough ER and upregulation of UPR-associated genes and proteins. RT-PCR of corneal endothelial cells from L450W and mutant mice at 40 weeks revealed 2.1-fold upregulation of the autophagy marker Dram1 (610776).
In 15 Korean patients from 6 pedigrees with early-onset Fuchs endothelial corneal dystrophy (FECD1; 136800) and 2 Korean patients with sporadic FECD, Mok et al. (2009) identified heterozygosity for a c.1370_1371CA-GT transversion in exon 2 of the COL8A2 gene, resulting in a gln455-to-val (Q455V) substitution in the triple-helical domain. The mutation, which segregated with disease in the families, was not found in 73 Korean controls without corneal disease.
Biswas, S., Munier, F. L., Yardley, J., Hart-Holden, N., Perveen, R., Cousin, P., Sutphin, J. E., Noble, B., Batterbury, M., Kielty, C., Hackett, A., Bonshek, R., Ridgway, A., McLeod, D., Sheffield, V. C., Stone, E. M., Schorderet, D. F., Black, G. C. M. Missense mutations in COL8A2, the gene encoding the alpha-2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum. Molec. Genet. 10: 2415-2423, 2001. [PubMed: 11689488] [Full Text: https://doi.org/10.1093/hmg/10.21.2415]
Gottsch, J. D., Sundin, O. H., Liu, S. H., Jun, A. S., Broman, K. W., Stark, W. J., Vito, E. C. L., Narang, A. K., Thompson, J. M., Magovern, M. Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of Fuchs corneal dystrophy. Invest. Ophthal. Vis. Sci. 46: 1934-1939, 2005. [PubMed: 15914606] [Full Text: https://doi.org/10.1167/iovs.04-0937]
Jun, A. S., Meng, H., Ramanan, N., Matthaei, M., Chakravarti, S., Bonshek, R., Black, G. C. M., Grebe, R., Kimos, M. An alpha 2 collagen VIII transgenic knock-in mouse model of Fuchs endothelial corneal dystrophy shows early endothelial cell unfolded protein response and apoptosis. Hum. Molec. Genet. 21: 384-393, 2012. [PubMed: 22002996] [Full Text: https://doi.org/10.1093/hmg/ddr473]
Kobayashi, Fujiki, K., Murakami, A., Kato, T., Chen, L.-Z., Onoe, H., Nakayasu, K., Sakurai, M., Takahashi, M., Sugiyama, K., Kanai, A. Analysis of COL8A2 mutation in Japanese patients with Fuchs' endothelial dystrophy and posterior polymorphous dystrophy. Jpn. J. Ophthal. 48: 195-198, 2004. [PubMed: 15175909] [Full Text: https://doi.org/10.1007/s10384-003-0063-6]
Liskova, P., Prescott, Q., Bhattacharya, S. S., Tuft, S. J. British family with early-onset Fuchs' endothelial corneal dystrophy associated with p.L450W mutation in the COL8A2 gene. Brit. J. Ophthal. 91: 1717-1718, 2007. [PubMed: 18024822] [Full Text: https://doi.org/10.1136/bjo.2007.115154]
Magovern, M., Beauchamp, G. R., McTigue, J. W., Fine, B. S., Baumiller, R. C. Inheritance of Fuchs' combined dystrophy. Ophthalmology 86: 1897-1923, 1979. [PubMed: 399801] [Full Text: https://doi.org/10.1016/s0161-6420(79)35340-4]
Meng, H., Matthaei, M., Ramanan, N., Grebe, R., Chakravarti, S., Speck, C. L., Kimos, M., Vij, N., Eberhart, C. G., Jun, A. S. L450W and Q455K Col8a2 knock-in mouse models of Fuchs endothelial corneal dystrophy show distinct phenotypes and evidence for altered autophagy. Invest. Ophthal. Vis. Sci. 54: 1887-1897, 2013. [PubMed: 23422828] [Full Text: https://doi.org/10.1167/iovs.12-11021]
Mok, J.-W., Kim, H.-S., Joo, C.-K. Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients. Eye 23: 895-903, 2009. [PubMed: 18464802] [Full Text: https://doi.org/10.1038/eye.2008.116]
Muragaki, Y., Jacenko, O., Apte, S., Mattei, M.-G., Ninomiya, Y., Olsen, B. R. The alpha-2(VIII) collagen gene: a novel member of the short chain collagen family located on the human chromosome 1. J. Biol. Chem. 266: 7721-7727, 1991. [PubMed: 2019595]
Muragaki, Y., Mattei, M.-G., Yamaguchi, N., Olsen, B. R., Ninomiya, Y. The complete primary structure of the human alpha-1(VIII) chain and assignment of its gene (COL8A1) to chromosome 3. Europ. J. Biochem. 197: 615-622, 1991. [PubMed: 2029894] [Full Text: https://doi.org/10.1111/j.1432-1033.1991.tb15951.x]