Molecular Genetic Analyses Of A Family With Congenital Cataract

Congenital cataract is one of the main causes of child blindness. Congenital cataract can be caused by variety of factors, which result in opacity of lens and affect it's transparence. Genetic factors play an important role in development of congenital cataract. The common inheritance pattern of congenital cataract is autosomal dominant, but autosomal recessive and X-linked patterns have been also reported. Inherited congenital cataract shows both genetic and clinical heterogeneity. The same phenotype of cataract in different patients can be caused by mutations in different genes or by different mutations in the same gene. On the other hand, the phenotypes vary dramatically in different individuals with the same mutation.To date, about 40 genetic loci have been identified to be linked with cataract, and 19 disease-causing genes have been identified. However, many families are not linked to the known cataract loci, indicating that more cataract genes remain to be identified.We characterized a large Chinese Han family with autosomal dominant congenital cataract. Linkage analysis with markers in known cataract genes excluded all of them, indicating that the Chinese family is associated with a new cataract gene.A genome-wide linkage scan was then used to map the chromosomal location of the new cataract gene in the Chinese family. The gene was found to be on chromosome 1 and flanked by two markers D1S489 and D1S3669. Further genotyping of two single nucleotide polymorphisms (SNPs) in the region by direct DNA sequence analysis defined the linkage region to IIP45-HSPB7. Further fine linkage mapping analysis was carried out using many SNPs in the region, which narrowed the linkage region between rs677769 and HSPB7. The interval is about 1.8Mb in length within 1p36.21-1p36.13, which is small enough to be appropriate for follow up mutational analysis to identify the disease-causing gene.Direct DNA sequence analysis of 20 known genes within the shortest linkage interval did not reveal any disease-causing mutation. These results suggest that the new cataract gene is an unknown or putative gene within 1p36.21-1p36.13, and mutational analysis in these unknown or putative genes is expected to result in the identification of a novel gene for cataract..These results provide a foundation for finding a new gene for cataract. Identification of the new cataract gene and the follow up functional studies will provide important insights into the molecular mechanisms for cataract, which may lead to new genetic testing and development of new treatment for cataract.