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L. J. Abu Safieh, A. Khan, B. Alalem, F. Alkuraya; Identification of a Novel CRYAB Mutation Associated with Autosomal Recessive Cataract in a Saudi Family. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4126.
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Cataract is a clinically and genetically heterogenous eye disease mainly characterized by opacity and light scattering of the lens, which occurs as a result of protein aggregation in the lens. The majority of hereditary cataracts are inherited as autosomal dominant; however, it can also be inherited as autosomal recessive or as X-linked manner. To date, 39 loci have been associated with the different forms of cataract. Lens proteins alone, including crystallins, account for approximately 70% of congenital cataract. The aim of this study was to characterize the genetic bases of congenital cataract in a Saudi family with 6 affected individuals.
Homozygousity mapping was used to analyze the SNP data generated by the 250K SNP microarrays. Automated Direct sequencing was used to screen for mutations in the likely candidate genes as determined by the blocks of homozygoustiy. Protein sequence alignment was performed using the multalin software v.5.4.1 to establish conservation of the mutated amino acid.
Homozygoisity mapping identified a common region in all affected individuals on Chromosome 11 q21-23spanning a previously reported cataract gene; CRYAB. This was also confirmed when easylinkage software was used. Direct sequencing of the CRYAB gene identified a c. 166C <T transition substitution resulting in a missense mutation changing the amino acid from Arginine to Tryptophan (R56W).This sequence alteration was not found in 150 Saudi controls. This result excludes the R56W mutation from being a rare polymorphism and strongly suggests that it is responsible for the disease phenotype in this Saudi family. Protein alignment showed that R56 is conserved across different species
In this study we are reporting the results of linkage analysis of a family with autosomal recessive cataract and show a novel genetic defect is a homozygous missense mutation in CRYAB. We find no evidence of muscle involvement in any of the patients but some manifest retinal pathology. We take advantage of the recently gained knowledge on the structure and function of this small heat shock protein to speculate on the potential mutational mechanism.This is the first report to implicate CRYAB in autosomal recessive cataract.
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