Inheritance of a NovelCOL8A2Mutation Defines a Distinct Early-Onset Subtype of Fuchs Corneal Dystrophy

Abstract

PURPOSE.To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD). METHODS.DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet's membrane that are characteristic of FCD. RESULTS.Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families. CONCLUSIONS.A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD. (Invest Ophthalmol Vis Sci. 2005;46:1934 -1939) DOI: 10.1167/iovs.04-0937 F uchs corneal dystrophy (FCD) is a primary disorder of the endothelium that leads to progressive edema of the corneal stroma (OMIM 136800; Online Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/Omim/ provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD). Visual disability from this disease is currently the major reason for corneal transplantation.1 The initial stages of FCD typically begin in the fifth through seventh decades of life and are characterized by localized thickening of Descemet's membrane and the development of nodular excrescences called guttae. This early phase is followed by long-term decreases in the density and ion transport functions of the overlying corneal endothelial cells, which allows excess water to accumulate in the cornea.2-8 Several reports, including the original description by Fuchs, have indicated that two to three times as many females as males are affected by the disease. 2,7,9 As many as 50% of clinical cases of FCD may show familial clustering, 9 and the disease generally follows an autosomal dominant pattern of inheritance. 10 -15 Nearly all these families show inheritance of late-onset FCD, whereas rare cases 12,14 show disease onset as early as the first decade, with extensive corneal edema by the third ...

Five children with deletions of 1p34.3 encompassing AGO1 and AGO3

“…Of these genes, only COL8A2 has been linked to a phenotype in humans. Heterozygous point variants in COL8A2 have been identified in individuals with early onset Fuchs endothelial corneal dystrophy (FECD), [11][12][13] a relatively common condition affecting approximately 5% of the US population in which bilateral progressive loss of corneal endothelium occurs. 12 Mouse models of COL8A2 missense variants recapitulate the disease phenotype.…”

“…Heterozygous point variants in COL8A2 have been identified in individuals with early onset Fuchs endothelial corneal dystrophy (FECD), [11][12][13] a relatively common condition affecting approximately 5% of the US population in which bilateral progressive loss of corneal endothelium occurs. 12 Mouse models of COL8A2 missense variants recapitulate the disease phenotype. 14 None of the patients described carry a diagnosis of corneal dystrophy, however, all five are younger than the typical age of onset for FECD, in which early-onset disease typically manifests in the third decade of life.…”

“…14 None of the patients described carry a diagnosis of corneal dystrophy, however, all five are younger than the typical age of onset for FECD, in which early-onset disease typically manifests in the third decade of life. [11][12][13] Three mammalian AGO genes (AGO 1, 3, and 4) reside in a cluster of closely related family members on chromosome 1p35p34. Two of the three genes, AGO1 and AGO3, fall within the deleted region shared by our patients and are thus of particular interest.…”

Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients

“…5 FECD generally begins in the fifth decade of life and can progress slowly over the next two to three decades. 6,7 Although rare, there is also an early onset form of this disease. 2,7,8 Although its pathogenesis has not been clearly elucidated, FECD is known to be an autosomal dominant disease with high penetrance that develops independently from systemic or environmental factors.…”

Polymorphisms of the Apoptosis-Related FAS and FAS Ligand Genes in Keratoconus and Fuchs Endothelial Corneal Dystrophy

“…Linkage studies of large multigenerational families with late-onset FECD identified several chromosomal regions on chromosomes 1, 5, 8 and X to be associated with the disease (Sundin et al 2006a, b;Afshari et al 2009). A strong association between FECD and genetic variants of the COL8A2 (collagen type VIII α2) gene was reported (Biswas et al 2001;Kobayashi et al 2004;Gottsch et al 2005).…”