Autosomal recessive congenital cataract linked to EPHA2 in a consanguineous Pakistani family

Abstract

Purpose: To investigate the genetic basis of autosomal recessive congenital cataracts in a consanguineous Pakistani family.

Methods: All affected individuals underwent a detailed ophthalmological and clinical examination. Blood samples were collected and genomic DNAs were extracted. A genome-wide scan was performed with polymorphic microsatellite markers. Logarithm of odds (LOD) scores were calculated, and Eph-receptor type-A2 (EPHA2), residing in the critical interval, was sequenced bidirectionally.

Results: The clinical and ophthalmological examinations suggested that all affected individuals have nuclear cataracts. Genome-wide linkage analyses localized the critical interval to a 20.78 cM (15.08 Mb) interval on chromosome 1p, with a maximum two-point LOD score of 5.21 at theta=0. Sequencing of EPHA2 residing in the critical interval identified a missense mutation: c.2353G>A, which results in an alanine to threonine substitution (p.A785T).

Conclusions: Here, we report for the first time a missense mutation in EPHA2 associated with autosomal recessive congenital cataracts.

Figure 1

Pedigree drawing and haplotypes of chromosome 1p markers of family PKCC118. Squares are males, circles are females, and filled symbols are affected individuals; the double line between individuals indicates consanguinity and the diagonal line through a symbol is a deceased family member. The haplotypes of 12 adjacent chromosome 1p microsatellite markers are shown; alleles forming the risk haplotype are shaded black, while alleles not co-segregating with cataract are shown in white.

Figure 2

Slit lamp photographs of the affected individuals of family PKCC118. A: Individual 19 and B: individual 20 of PKCC118 reveal nuclear cataracts that developed in the early years of their lives.

Figure 3

Mutational analyses of Eph-receptor type-A2 in family PKCC118. A: Sequence chromatograms of wild type allele in individual 15 showing the translation of alanine. B: Individual 10, and C: individual 20 are heterozygous and homozygous for c.2353 G>A transition, respectively, which predicts the substitution of an alanine residue for a threonine residue at position 785 (Ala785Thr) in the Eph-receptor type-A2.

Figure 4

Sequence alignment of amino acids of the Eph-receptor type-A2 illustrating conservation of the amino acid alanine at position 785 and its neighboring amino acids. The organisms shown in blue are primates, in green are placental mammals, and in purple are vertebrates. The arrow points to A785 that is mutated in the family, PKCC118.