Novel mutation in the gamma-S crystallin gene causing autosomal dominant cataract

Abstract

Purpose: To identify the underlying genetic defect in a north Indian family with seven members in three-generations affected with bilateral congenital cataract.

Methods: Detailed family history and clinical data were recorded. Linkage analysis using fluorescently labeled microsatellite markers for the already known candidate gene loci was performed in combination with mutation screening by bidirectional sequencing.

Results: Affected individuals had bilateral congenital cataract. Cataract was of opalescent type with the central nuclear region denser than the periphery. Linkage was excluded for the known cataract candidate gene loci at 1p34-36, 1q21-25 (gap junction protein, alpha 8 [GJA8]), 2q33-36 (crystallin, gamma A [CRYGA], crystallin, gamma B [CRYGB], crystallin, gamma C [CRYGC], crystallin, gamma D [CRYGD], crystallin, beta A2 [CRYBA2]), 3q21-22 (beaded filament structural protein 2, phakinin [BFSP2]), 12q12-14 (aquaporin 0 [AQP0]), 13q11-13 (gap junction protein, alpha 3 [GJA3]), 15q21-22, 16q22-23 (v-maf musculoaponeurotic fibrosarcoma oncogene homolog [MAF], heat shock transcription factor 4 [HSF4]), 17q11-12 (crystallin, beta A1 [CRYBA1]), 17q24, 21q22.3 (crystallin, alpha A [CRYAA]), and 22q11.2 (crystallin, beta B1 [CRYBB1], crystallin, beta B2 [CRYBB2], crystallin, beta B3 [CRYBB3], crystallin, beta A4 [CRYBA4]). Crystallin, alpha B (CRYAB) at chromosome 11q23-24 was excluded by sequence analysis. However, sequencing the candidate gene, crystallin, gamma S (CRYGS), at chromosome 3q26.3-qter showed a heterozygous c.176G-->A change that resulted in the replacement of a structurally highly conserved valine by methionine at codon 42 (p.V42M). This sequence change was not observed in unaffected family members or in the 100 ethnically matched controls.

Conclusions: We report a novel missense mutation, p.V42M, in CRYGS associated with bilateral congenital cataract in a family of Indian origin. This is the third report of a mutation in this exceptional member of the beta-/gamma-crystallin superfamily and further substantiates the genetic and clinical heterogeneity of autosomal dominant cataract.

Figure 1

Pedigree of an Indian family with autosomal dominant congenital cataract (ADCC) is shown. The proband (III:2) is indicated by an arrow. Filled squares and circles represent affected males and females, respectively. Seven members in three generations were affected with bilateral cataract since childhood. Except the proband (III:2), all other affected members (I:4, II:7, II:8, II:9, II:12, III:2, III:3) were operated for bilateral congenital cataract in the first decade of their life.

Figure 2

Slit lamp photograph of affected lens. A slit lamp photograph is shown of the affected lens (left eye) in the three-year-old proband (III:2, Figure 1). Cataract is of the opalescent type. The central nuclear region is more dense than the periphery.

Figure 3

Mutation analysis of CRYGS in an unaffected and an affected individual. The wild-type G in the sequence of the unaffected individual (II:6; forward strand) and the heterozygous c. 176G→A change resulting in the substitution of valine-42 by methionine (p.V42M) in the affected individual (III:2; forward strand) are indicated by arrows.

Figure 4

Amino acid sequence alignment of CRYGS. Multiple alignment of partial amino acid sequences of CRYGS from different Homo sapien γ crystallins (γ S, γ A, γ B, γ C, γ D) and from different species indicate that valine at position 42 (red) is highly conserved. The valine to methionine substitution at codon 42 (p.V42M) in γ S in the proband’s (III:2) sequence is also highlighted (pink).