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C. Pang, L. Y. Zhang, D. S. P. Fan, C. K. S. Leung, J. P. Tong, P. O. S. Tam, G. H. F. Yam, D. S. C. Lam; Genetics Study and Mutation Functional Analysis of Autosomal Dominant Congenital Cataract. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2444.
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To identify the disease-causing mutation for Chinese autosomal dominant congenital cataract (ADCC) families, and investigate the functional alteration of mutant genes.
Six three- or four-generation Chinese ADCC families were recruited for this study. All members were undertaken careful clinical examinations. Whole blood samples or buccal swab samples were collected to extract DNA. Two-point linkage analysis with SNPs and microsatellite markers and candidate gene sequencing were applied to find the causative mutation. Wild type and mutant gene recombinant constructs were built, and transfected into mammalian cells. Total protein were harvested and separated by solubility with Triton-X. Western blot was done to detect the expression change of wild type protein and mutant protein.
The clinical features of 6 families were different, including one coppock-like cataract, two posterior polar cataract, one zonular sutural cataract, one coralliform cataract, and one coronary cataract families. All affected individuals had lens opacity in both eyes and had no systemic disease. 15 candidate genes were excluded in the coppock-like cataract family, one posterior polar cataract family, and the coronary family. One sequence change C103T (R12C) of CRYAA cosegregated with disease in one posterior polar cataract family. Another 510delG (G165fs) altering of CRYGD was found to be associated with the zonular sutural cataract family. One known mutation of P23T in CRYGD was detected to be the disease causing mutation for the coralliform cataract family. Wild type and mutant recombinant plasmid of CRYAA and CRYGD were built. Both proteins were successfully expressed by CHO cells in vitro.
For posterior polar cataract, only CRYAB and PITX3 were reported to be related to this specific phenotype before. Our study provided CRYAA as the third causative gene, moreover, R12C was a novel mutation in this gene. And in another posterior polar cataract family, all 15 known genes have excluded, which indicated there must be another novel gene may responsible for the disease. So, in Chinese population posterior polar cataract has great genetic heterogeneity. We also found a novel mutation 510delG of CRYGD which was related to the zonular sutural cataract by the transcription of abnormal shorter protein. Functional analysis of these two mutations is ongoing.
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