Analysis of Mutations in the Gene for the Alpha 2 Chain of Type VIII Collagen (COL8A2) in Families and Cases With Fuchs’ Endothelial Corneal Dystrophy

Abstract

Abstract: : Purpose: Fuchs’ endothelial corneal dystrophy (FECD; MIM136800) is a common disease affecting approximately 1% of the general US population. An earlier report described mutations in the COL8A2 gene in early–onset families with FECD. A second report in the Japanese population has been unable to corroborate these mutations. The lack of confirmation is not surprising because the original authors reported genetic heterogeneity with approximately 8% of FECD cases bearing mutations in COL8A2. To further characterize the importance of this gene in FECD, index cases derived from a multi–center study to map genes for Fuchs’ Dystrophy were scanned for mutations. Methods: Cases with advanced FECD were identified at 3 clinical centers and the extent of familial clustering characterized using a clinical measure of severity as a semi–quantitative trait. Family history, clinical, and other demographic information were collected using a standardized instrument. Histopathologic confirmation of advanced index cases was obtained. Blood samples were collected for molecular genetic analyses. Sequencing of PCR products of the COL8A2 gene was performed to identify mutations. Results: FECD patients (N=26, 24 probands enrolled in our family study) were scanned for the gln455lys mutation at position 1364 of the COL8A2 gene. We did not find the gln455lys mutation in this sample. Our sample was generally older than the sample described by Biswas et al (2001). Of the 24 FECD family probands, 2 African American (2 female; mean age = 77.5 yrs), 19 Caucasian (13 female, mean age = 65.1yrs; 6 male, mean age = 58.8 yrs), 1 Hispanic (female; age = 72 yrs) and 2 other (female; mean age = 60 yrs) were enrolled. The pathogic confirmation rate was 100%. COL8A2 has two exons, and using sequencing approximately 40% of the gene has been scanned, but no mutations are observed thus far. Other regions of this gene may bear mutations and additional scanning is ongoing. We are also in the process of identifying additional families and sporadic cases. Mutations in COL8A2 will also be investigated in the larger sample. Conclusions: We were unable to identify mutations in the COL8A2 gene in 26 index cases with FECD. We conclude that FECD is a genetically heterogeneous disorder and mutations in other regions of COL8A2 or in other genes may cause the disease.

Keywords: cornea: endothelium • genetics • mutations