Cataract 6, Multiple Types

A number sign (#) is used with this entry because multiple types of cataract are caused by heterozygous mutation in the EPHA2 gene (176946) on chromosome 1p36.

Description

Mutations in the EPHA2 gene have been found to cause multiple types of cataract, which have been described as posterior polar, congenital total, complete, and age-related cortical.

The preferred title/symbol of this entry was formerly 'Cataract, posterior polar, 1; CTPP1,' and 'Cataract, Age-Related Cortical, 2; ARCC2' was formerly a distinct entry.

Clinical Features

In Nettleship's family (Nettleship (1909, 1912)), congenital posterior polar opacities were present and scattered cortical opacities appeared in childhood and progressed to total cataract. Tulloh (1955) described 15 affected in 5 generations. Valk and Binkhorst (1956) described associated choroideremia and myopia in 2 generations.

Ionides et al. (1997) reported 10 affected members of a family with autosomal dominant posterior polar cataract. The opacity, which was bilateral in all cases, consisted of a single well-defined plaque confined to the posterior pole of the lens and varied from 0.5 to 3 mm in diameter. Because of its proximity to the optical center of the eye, posterior polar cataract can have a marked effect on visual acuity. Hospital records indicated that the opacity was usually present at birth or developed within the first few months of life but did not progress with age to other regions of the lens. There was no evidence of posterior lenticonus or high myopia and no family history of other ocular or systemic abnormalities.

McKay et al. (2005) studied a 6-generation Tasmanian family segregating autosomal dominant congenital cataract, previously studied by Burdon et al. (2004), in which most of the 13 patients were elderly and aphakic with no preoperative clinical notes available, although cataracts in 2 patients had been described as 'complete.' Most affected individuals were diagnosed shortly after birth, and the mean age of cataract surgery was 3 years, 4 months. Of the 12 aphakic patients, 11 had nystagmus, 2 had exotropia, 4 had esotropia, and 4 had bilateral aphakic glaucoma. One obligate carrier was phakic with good vision, but unavailable for slit-lamp examination. No other ocular or systemic abnormalities were noted in this family.

Shiels et al. (2008) studied a 4-generation Caucasian family segregating autosomal dominant posterior polar cataracts with no systemic abnormalities. Ophthalmic records indicated that the cataracts usually presented in both eyes as disc-shaped posterior subcapsular opacities with evidence of posterior lenticonus. In 3 affected individuals, opacification progressed to affect the central (nuclear) and anterior polar regions of the lens. One affected individual also had monocular amblyopia, and 2 others developed strabismus requiring corrective surgery. Age at diagnosis ranged from birth to 15 years, and age at surgery ranged from 0 to 44 years; post-surgical corrected visual acuity varied from 20/20 to 20/70 in the better eye.

Mapping

Ionides et al. (1997) mapped autosomal dominant posterior polar cataract (symbolized CPP by them) to chromosome 1p on the basis of studies in a single family. Significantly positive lod scores were obtained for markers D1S508 and D1S468; multipoint analysis gave a maximum lod score of 3.48 (theta = 0.07) between markers D1S508 and D1S468. From haplotype data, however, Ionides et al. (1997) concluded that the CPP locus probably lies in the telomeric interval 1pter-D1S2845, which includes the locus for the clinically distinct Volkmann congenital cataract (CCV; 115665).

In a 6-generation Tasmanian family segregating autosomal dominant congenital total cataract, previously studied by Burdon et al. (2004) and found to be negative for mutation in 5 known crystallin genes, McKay et al. (2005) performed linkage analysis using microsatellite markers across the known cataract loci and obtained 2-point lod scores of 4.21 and 3.23 for D1S507 and D1S2644 (theta = 0.0), respectively, at the telomere of chromosome 1p. Multipoint analysis yielded maximum location and lod scores of 5.61 and 5.44, respectively. Recombination in 2 affected individuals defined a 6-Mb critical region, between centromeric marker D1S199 and telomeric marker D1S228, that contains 30 named genes, of which 18 are known to be expressed in the eye. McKay et al. (2005) noted that this region is 6 Mb telomeric to that defined by Eiberg et al. (1995) for CCV and concluded that there are at least 2 genes predisposing to ADCC on the telomeric region of chromosome 1p.

Shiels et al. (2008) performed genomewide linkage analysis in a 4-generation Caucasian family with autosomal dominant posterior polar cataracts and obtained a parametric multipoint lod score of 3.3 on chromosome 1p; haplotype analysis defined an approximately 10-Mb common disease interval between rs707455 and rs477558 on 1p36 that cosegregated with disease in all 12 affected individuals. Genotyping of all 18 family members with simple tandem repeat (STR) markers confirmed that the cataract locus resides in an approximately 12-Mb interval between D1S214 and D1S2644, coincident with the SNP interval on 1p36.

Shiels et al. (2008) performed candidate-gene association analysis in a case-control cohort with age-related nuclear and cortical cataracts and found suggestive association with SNPs in the EPHA2 region of chromosome 1p (p less than 0.007 at rs11260867 for cortical cataracts and p less than 0.01 at rs7543472 for cortical and/or nuclear cataracts).

Zhang et al. (2009) performed 2-point linkage analysis in a 5-generation Han Chinese family segregating autosomal dominant posterior polar congenital cataract and obtained a maximum lod score of 3.61 (theta = 0.0) at D1S552 on chromosome 1p36. Haplotype analysis together with published data from the Australian family studied by McKay et al. (2005) reduced the critical region to a 4-Mb interval between markers D1S436 and D1S199.

Jun et al. (2009) identified families from the Beaver Dam Eye Study (BDES, performed in the population of Beaver Dam, Wisconsin) with linkage to markers on chromosome 1p36 (Iyengar et al., 2004) and resequenced the EPHA2 gene in 34 individuals. Of the 13 EPHA2 variants discovered or confirmed, 4 were genotyped in 1,401 individuals from 494 BDES families, and a nonsynonymous variant (R721Q; 176946.0005) demonstrated the strongest association (p = 2 x 10(-8) for cortical cataract, p = 8 x 10(-5) for severe cortical cataract). Jun et al. (2009) then genotyped those 4 SNPs and 15 additional SNPs covering at least 90% of the EPHA2 gene in the BDES families and 2 more Caucasian populations (185 individuals from 172 families in the United Kingdom Twin Eye Study, and 1,470 unrelated individuals in the Australian Blue Mountains Eye Study), and found that the EPHA2 gene contains at least 2 relatively independent blocks of linkage disequilibrium, one at the 5-prime end and another at the 3-prime end. Single SNP association, haplotype association, and metaanalysis consistently demonstrated 2 independent association signals present in the 3-prime (rs7548209 and rs3754334) and the 5-prime (rs3768293, rs6603867, and rs6678616) regions of the gene, with rs6678616 showing the strongest association with age-related cortical cataract (combined p = 10(-4)).

Molecular Genetics

In a 4-generation Caucasian family with autosomal dominant posterior polar cataracts mapping to chromosome 1p36, Shiels et al. (2008) identified a heterozygous missense mutation in the EPHA2 gene (G948W; 176946.0001) that was not found in 192 controls. Candidate-gene association analysis in a case-control cohort with age-related cortical and nuclear cataracts showed suggestive association with SNPs in the EPHA2 region of chromosome 1p (p less than 0.007 at rs11260867 for cortical cataracts and p less than 0.01 at rs7543472 for cortical and/or nuclear cataracts).

In a 5-generation Han Chinese family segregating autosomal dominant posterior polar congenital cataract mapping to 1p36, Zhang et al. (2009) identified a heterozygous mutation in the EPHA2 gene (T940I; 176946.0002) that was present in all 7 affected family members but not detected in 6 unaffected family members or 202 unrelated Chinese controls. Zhang et al. (2009) then sequenced the EPHA2 gene in the British and Australian families with autosomal dominant cataract mapping to 1p, previously studied by Ionides et al. (1997) and McKay et al. (2005), respectively, and identified a heterozygous 2-bp deletion (176946.0003) and splice site mutation (176946.0004), respectively.

In a large family with age-related cortical cataract, Jun et al. (2009) sequenced the EPHA2 gene and found that a nonsynonymous variant, R721Q (176946.0005), cosegregated with the phenotype. The frequency of the rare 'A' allele in 3 independent Caucasian study populations from the United States, United Kingdom, and Australia was 0.6%, 0%, and 0.2%, respectively; the authors stated that 0.1% to 0.2% probably represents a true population estimate for this rare variant. The risk allele had 78% penetrance in heterozygous individuals whose age was 70 years or more. Functional analysis demonstrated that R721Q significantly alters EPHA2 signaling and cellular regulation in vitro.