Corneal Dystrophy, Fuchs Endothelial, 1

A number sign (#) is used with this entry because of evidence that Fuchs endothelial corneal dystrophy-1 (FECD1) is caused by heterozygous mutation in the COL8A2 gene (120252) on chromosome 1p34.

Description

Fuchs endothelial corneal dystrophy (FECD) is a progressive, bilateral condition characterized by dysfunction of the corneal epithelium, leading to reduced vision. The prevalence of FECD has been estimated at about 5% among persons over the age of 40 years in the United States. The vision loss in patients with FECD results from a loss of corneal transparency associated with irregularity of inner corneal layers in early disease and edema of the cornea in advanced disease. Ultrastructural features of FECD include loss and attenuation of endothelial cells, with thickening and excrescences of the underlying basement membrane. These excrescences, called guttae, are the clinical hallmark of FECD and become more numerous with progression of the disease. As the endothelial layer develops confluent guttae in the central cornea, the cells are no longer able to keep the cornea dehydrated and clear (summary by Baratz et al., 2010).

Genetic Heterogeneity of Fuchs Endothelial Corneal Dystrophy

More common, late-onset forms of FECD have been shown to be caused by mutation in the SLC4A11 gene (610206) on chromosome 20p13 (FECD4; 613268), in the ZEB1 gene (189909) on chromosome 10p11.2 (FECD6; 613270), and in the AGBL1 gene (615496) on chromosome 15q25 (FECD8; 615523).

Other loci for late-onset FECD have been identified on chromosomes 13pter-q12.13 (FECD2; 610158), 18q21.2-q21.32 (FECD3; 613267), 5q33.1-q35.2 (FECD5; 613269), and 9p (FECD7; 613271).

Clinical Features

Gottsch et al. (2005) restudied a family with early-onset Fuchs endothelial corneal dystrophy that had been reported by Magovern et al. (1979). They noted that the corneal guttae were small, rounded, and associated with the endothelial cell center, whereas the guttae seen in common FECD are larger, sharply peaked, and initially positioned at edges of endothelial cells. Affected family members were found to have a mutation in the COL8A2 gene (120252.0003). Among affected family members were children as young as 3 years. All who were in the early stages of the disease in 1979 had progressed to corneal decompensation, and several had undergone penetrating keratoplasty. Gottsch et al. (2005) noted that this natural history fit well with the early-onset family with a mutation in the COL8A2 gene (120252.0001) reported by Biswas et al. (2001) in which FECD was diagnosed in individuals from ages 21 to 48, and those in their 30s and 40s had advanced stages of the disease. The profile of age and disease severity for the FECD kindred restudied by Gottsch et al. (2005) suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FECD patients in 62 other families in which mutations in COL8A2 were not found. The disorder progressed from early to late stages in 25 years, a rate similar to that estimated for the more common late-onset FECD. Gottsch et al. (2005) compared the sex distribution in their early-onset FECD kindred with that of 62 late-onset FECD pedigrees. There was an approximately 1:1 female:male ratio in the early-onset pedigree compared with a 2:1 ratio in the late-onset families.

Liskova et al. (2007) reported a 3-generation British family in which 4 individuals had Fuchs endothelial corneal dystrophy. A 79-year-old man was diagnosed with 'endothelial pathology' at 23 years of age; at age 75, he underwent left penetrating keratoplasty with cataract extraction and intraocular lens implantation. Histology of the cornea showed thickening of the Descemet membrane without cornea guttata; however, guttae were present in his right eye. The proband's 53-year-old daughter experienced visual deterioration in her mid-twenties due to bilateral corneal edema; she underwent right penetrating graft at 34 years of age, and left penetrating keratoplasty at age 41. Her affected son showed endothelial changes at age 9 years but still had 20/20 vision at age 18. Examination of the proband's asymptomatic 55-year-old son showed endothelial pleomorphism and guttae located both centrally and within the borders of endothelial cells.

Hecker et al. (2011) studied whether keratocyte populations were different in 11 corneas excised during penetrating keratoplasty for FECD corneas, 5 control corneas of eyes enucleated for choroidal melanoma, and 20 age-matched control corneas. By histology, the mean (SD) number of cells in a full-thickness column of stroma in FECD (12,215 (1394) cells) was less than in control corneas (15,628 (710) cells; p less than 0.001). The mean (SD) number of keratocytes in the anterior 10% of the corneal stroma with FECD (682 (274) cells) was less than in the control corneas measured using histology (1858 (404) cells; p less than 0.001) and by confocal microscopy (1481 (397) cells; p less than 0.001). Hecker et al. (2011) concluded that keratocytes were depleted by 54 to 63% in the anterior 10% of the stroma of corneas that required penetrating keratoplasty for FECD. They suggested that keratocyte loss might contribute to anterior stromal changes that persist and degrade vision after endothelial keratoplasty.

Wacker et al. (2015) determined anterior and posterior corneal wavefront higher-order aberrations (HOAs) in 108 eyes (62 subjects) with a range of severity of FECD and 71 normal eyes (38 subjects). Total anterior corneal HOAs were increased in moderate and advanced FECD compared with controls. Total posterior corneal HOAs were increased in mild, moderate, and advanced FECD compared with controls. Both anterior and posterior corneal backscatter were greater for all severities of FECD compared with controls. Wacker et al. (2015) suggested that early onset of HOAs in FECD might contribute to the persistence of HOAs and incomplete visual rehabilitation after endothelial keratoplasty.

Biochemical Features

Wang et al. (2007) described the histopathologic features of Descemet membrane (DM) obtained from FECD corneas undergoing Descemet stripping with endothelial keratoplasty (DSEK) and assessed the presence of advanced glycation end products (AGEs) and their receptors (RAGEs) in FECD endothelium and DM. Histopathologic assessment of specimens from FECD patients revealed thickening and nodularity of DM and loss of endothelial cells. Immunohistochemical staining of FECD DM for AGE, RAGE, and galactin-3 (AGE-R3) showed an abundance of AGEs in the anterior portion of DM, mild positivity for RAGE, and moderate positivity for AGE-R3. Wang et al. (2007) concluded that the presence of AGEs, RAGE, and AGE-R3 in DM and corneal endothelium of FECD patients supported a link between accumulation of advanced glycation end products, oxidative stress, and corneal endothelial cell apoptosis in the pathogenesis of FECD.

Azizi et al. (2011) compared susceptibility of FECD and normal corneal endothelial cells (CECs) to oxidative stress, and studied the mechanism of oxidative stress-induced apoptosis in FECD-affected endothelium. Immortalized normal and FECD human corneal endothelial cell lines were exposed to oxidative stress. FECD CECs were more susceptible to oxidative DNA damage and oxidative stress-induced apoptosis than normal cells. Increased activation of transcription factor p53 (191170) in FECD suggested to Azizi et al. (2011) that it was p53 that mediated cell death in susceptible CECs. Azizi et al. (2011) concluded that p53 plays a critical role in complex mechanisms regulating oxidative stress-induced apoptosis in FECD.

Molecular Genetics

Biswas et al. (2001) conducted a genomewide search of a 3-generation family with early-onset FECD and identified a critical region of 6 to 7 cM at chromosome 1p34.3-p32, which includes the COL8A2 (120252) gene. COL8A2 encodes a short-chain collagen which is a component of endothelial basement membranes and which represented a strong candidate gene. Analysis of its coding sequence defined a gln455-to-lys missense mutation (Q455K; 120252.0001) within the triple helical domain of the protein in this family. Mutation analysis in other patients demonstrated further missense substitutions in familial and sporadic cases of FECD, as well as in a single family with posterior polymorphous 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 endothelial 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 a leu450-to-trp amino acid substitution (L450W; 120252.0003).

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. The mutation, which segregated with disease in all 6 pedigrees, was not found in 73 Korean controls without corneal disease. Diagnosis was made in the third or fourth decade of life in the probands from the FECD families. Slit-lamp examination of a mutation-positive patient from 1 family showed corneal guttae on the posterior corneal surface, with the coarse and distinct pattern characteristic of early-onset disease.

Population Genetics

Minear et al. (2013) analyzed the COL8A2, SLC4A11, and ZEB1 genes in 47 African American probands with FECD, but identified no causative variants. The authors concluded that variation in these genes does not appear to significantly contribute to the genetic risk or FECD in African Americans.

Animal Model

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.