Dataset Information

Gamma-S crystallin gene (CRYGS) mutation causes dominant progressive cortical cataract in humans.

ABSTRACT:

Background

Congenital or childhood cataract is clinically and genetically a highly heterogeneous lens disorder in children. Autosomal dominant inheritance is most common.

Objective

To report the identification of a mutation in the human CRYGS gene.

Subjects and methods

A large six generation family affected by progressive polymorphic cortical cataract was investigated. After excluding loci for known cataract candidate genes using 39 fluorescent microsatellite markers, a whole genome scan was carried out.

Results

The disease was associated with inheritance of a 20.7 cM locus on chromosome 3q26.3-qter, with a maximum LOD score of 6.34 (theta = 0) at marker D3S1602. Haplotype analysis indicated that the disease gene lay at approximately 2.8 Mb physical intervals between D3S1571 and D3S3570 and contained CRYGS on 3q27.3. By sequencing the CRYGS gene, a distinct 1619G-->T (AC068631) heterozygous missense mutation in exon 2 was identified, co-segregating with the disease phenotype in this family and resulting in a glycine (GGC) to valine residue (GTC) substitution in codon 18 (NP_060011).

Conclusions

This report is the first description of a mutation in CRYGS with autosomal dominant cataract in humans.

SUBMITTER: Sun H

PROVIDER: S-EPMC1736139 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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Publications

Gamma-S crystallin gene (CRYGS) mutation causes dominant progressive cortical cataract in humans.

Sun H H Ma Z Z Li Y Y Liu B B Li Z Z Ding X X Gao Y Y Ma W W Tang X X Li X X Shen Y Y

Journal of medical genetics 20050901 9

<h4>Background</h4>Congenital or childhood cataract is clinically and genetically a highly heterogeneous lens disorder in children. Autosomal dominant inheritance is most common.<h4>Objective</h4>To report the identification of a mutation in the human CRYGS gene.<h4>Subjects and methods</h4>A large six generation family affected by progressive polymorphic cortical cataract was investigated. After excluding loci for known cataract candidate genes using 39 fluorescent microsatellite markers, a who ...[more]

PMID: 16141006

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Project description: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.

Project description:AIM:To identify mutations in the genes of a four-generation Chinese family with congenital membranous cataracts and investigate the morphologic changes and possible functional damage underlying the role of the mutant gene. METHODS:Whole exome analysis of thirteen members of a four-generation pedigree affected with congenital membranous cataracts was performed; co-segregation analysis of identified variants was validated by Sanger sequencing. All members underwent detailed physical and complete eye examinations. The physical changes caused by the mutation were analyzed in silico through homology modeling. The lens fiber block from a patient was observed under a scanning electron microscope (SEM). Cell membrane proteins and cytoplasmic proteins from the human lenses donated by one patient with cataract in this family and from the dislocated lens resulted from the penetrating ocular trauma of a patient unrelated with this family were extracted, and the expression and localization of MP20 and Cx46 were detected by Western blot (WB) assay in these proteins. RESULTS:A novel LIM2 heterozygous mutation (c.388C>T, p.R130C) was identified with congenital membranous cataracts inherited by an autosomal dominant (AD) pattern. Nystagmus and amblyopia were observed in all patients of this family, and exotropia and long axial length were observed in most patients. A/B ultrasound scan and ultrasound biomicroscopy revealed obvious thin crystalline lenses from 1.7 to 2.7 mm in central thickness in all cataract eyes. The bioinformatic analysis showed that the mutation was deleterious to the physiological function of LIM2-encoded MP20. Furthermore, by SEM, ultrastructure of the cataract nucleus showed that lens fiber cells (LFCs) remained morphologic characteristics of immature fiber cells, including flap cell surface with straight edges and lacking normal ball-and-socket joint boundaries, which implied that the differentiation of LFCs might be inhibited. Accumulation of MP20 and Cx46 in the cytoplasm was observed in the cytoplasm of the LFCs in human cataract lens. CONCLUSION:We identify a novel heterozygous LIM2 (c.388C>T, p.R130C) mutation inherited by an AD pattern. This LIM2 mutation causes the abnormal sub-localization of MP20 and Cx46 in LFCs resulting in membranous cataracts.

Dataset Information

Gamma-S crystallin gene (CRYGS) mutation causes dominant progressive cortical cataract in humans.

Background

Objective

Subjects and methods

Results

Conclusions

Publications

Gamma-S crystallin gene (CRYGS) mutation causes dominant progressive cortical cataract in humans.

Similar Datasets

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