A mutation in GJA8 (p.P88Q) is associated with "balloon-like" cataract with Y-sutural opacities in a family of Indian origin

Abstract

Purpose: To detect the underlying genetic defect in a family with three members in two generations affected with bilateral congenital cataract.

Methods: Detailed family history and clinical data were recorded. Mutation screening in the candidate genes, alphaA-crystallin (CRYAA), betaA1-crystallin (CRYBA1), betaB2-crystallin (CRYBB2), gammaA-gammaD-crystallins (CRYGA, CRYGB, CRYGC, and CRYGD), connexin-46 (GJA3), and connexin-50 (GJA8), was performed by bidirectional sequencing of the amplified products.

Results: Affected individuals had "balloon-like" cataract with prominent Y-sutural opacities. Sequencing of the candidate genes showed a heterozygous c.262C>A change in the gene for connexin 50 (GJA8), which is localized at 1q21, that resulted in the replacement of a highly conserved proline by glutamine (p.P88Q). This sequence change was not observed in 96 ethnically matched controls.

Conclusions: We report a p.P88Q mutation in GJA8 associated with Y-sutural cataract in a family of Indian origin. Mutations of the same codon have previously been described in British families with pulverulent cataract, suggesting that modifying factors may determine the type of cataract.

Figure 1

Pedigree of a family with individuals affected by bilateral congenital cataract. The pedigree of an autosomal dominant congenital cataract (ADCC) family shows three members in two generations as affected (filled squares and circle). The proband (III:2), who was diagnosed as bilaterally affected with congenital cataract at the age of seven years, is indicated with an arrow. His elder sister (III:1) was diagnosed with bilateral cataract when she was six years old. The affected father (II:3) of these children underwent cataract extraction in both of his eyes in the first decade of his life.

Figure 2

Photograph of cataract phenotypes observed in the present Indian family and in the British family having the identical mutation (p.P88Q) in GJA8. A: The slit lamp photograph (three-dimensional lens) of a patient shows very prominent feather-like sutural opacities. Apart from sutural opacities, riders are prominent. The inside of the semi-opaque fetal nucleus appeared optically empty. B: The photograph from the affected lens of an individual from the British autosomal dominant congenital cataract family with zonular pulverulent cataract [20] shows linear dense vertical opacities inside the fetal nucleus with embryonic nucleus remaining clear and without sutural opacities.

Figure 3

Partial DNA sequence of GJA8 from an unaffected and an affected individual. The wild type C in the sequence of the unaffected individual and the heterozygous c.262C>A change, which results in the substitution of proline by glutamine at amino acid position 88 (p.P88Q), in the affected individual are indicated by arrows. F=forward strand.