A novel connexin 50 gene (gap junction protein, alpha 8) mutation associated with congenital nuclear and zonular pulverulent cataract

Abstract

Purpose: To characterize the disease-causing mutations in four generations of a Chinese family affected with bilateral congenital nuclear and zonular pulverulent cataract.

Methods: Detailed family history and clinical data were recorded. The phenotype was documented using slit-lamp photography. Candidate genes were amplified using PCR and screened for mutations using bidirectional sequencing.

Results: Affected individuals had nuclear and zonular pulverulent cataract with Y-sutural opacities. Sequencing of the candidate genes revealed a heterozygous c. 139G>C change in the coding sequence of the connexin 50 gene (gap junction protein, alpha 8 [GJA8]), which results in the substitution of a wild-type aspartic acid with a histidine (D47H). This mutation cosegregated with all affected individuals in the family and was not found in unaffected family members or in 100 unrelated controls.

Conclusions: Our study has identified a novel connexin 50 gene (GJA8) mutation, resulting in the amino substitution p. D47H in a Chinese family with nuclear and zonular pulverulent congenital cataracts. This mutation is probably the causative lesion for the observed phenotype in this family.

Figure 1

Pedigree of autosomal dominant congenital cataract (ADCC). The proband is marked with an arrow. Squares and circles indicate men and women, respectively. Black and white symbols represent affected and unaffected individuals, respectively. The asterisks indicate family members who were enrolled in this study.

Figure 2

Slit-lamp photograph of the family members who had congenital nuclear and zonular pulverulent cataracts with Y-sutural opacities. The affected member IV:2 (C, D) had more severe nuclear opacities than her mother III:1 (A, B).

Figure 3

Forward and reverse sequence analysis of the affected and unaffected individuals in a Chinese family with autosomal dominant congenital cataract (ADCC), showing a G139C mutation of the connexin 50 gene (black arrows).

Figure 4

Boxes indicate regions with a helical secondary structure denoted as NTH, TM1, TM2, TM3, TM4, and a short helix in E1. The membrane region is depicted in light blue. Red letters: Previous connexin 50 gene mutations with congenital cataract in humans: R23T, I31T, V44E, W45S, G46V, D47N, D47Y, E48K, V64G, V79L, P88Q, P88S, P189L, R198W, R198Q, I247M, S258F, and S276F. Yellow letters: Previous connexin 50 gene mutations in the mouse: L7Q, G22R (Lop10 mouse), D47A (nuclear opacity 2, No 2 mouse), and S50P (L1 mouse). Red letter in yellow circle: the new mutation D47H in this family.