RPE65 Mutations May be a Common Cause of Leber Congenital Amaurosis in India

Abstract

Purpose: : To determine the prevalence of pathogenic variations in the gene encoding retinal pigment epithelium 65 (RPE65) in patients from India with Leber congenital amaurosis (LCA).

Methods: : Nine LCA families were recruited for the study based on clinical and pedigree analysis. The genomic DNA was extracted from the blood samples, screened for mutations in all 14 exons and the adjacent flanking intron regions of RPE65 gene by sequencing. Pathogenicity of the identified variations was confirmed by segregation analysis in families, screening ethnically matched controls and bioinformatics prediction.

Results: : Mutational screening of RPE65 gene revealed homozygous pathogenic variations in three families: two missense (p.Leu370His & p.Val473Asp) and one frameshift (p.Ser121PhefsX129) mutations. The novel, homozygous missense mutation, p.Leu370His was identified in two sibs from the same family. The age of diagnosis of the disease in this family was during infancy. Patient with p.Val473Asp missense mutation was a child of consanguineous union (first cousins). Deletion of nucleotide A at c.361, leading to frameshift was observed in a LCA patient. This resulted in a truncated protein consisting of 129 amino acids with 9 new amino acids prior to stop codon. A heterozygous putative polymorphism (p.Asp321Lys) was identified in one LCA patient. The contribution of RPE65 gene mutations to LCA cases in our study group is found to be high (approximately 33%) compared to previous reports.

Conclusions: : RPE65

Keywords: genetics • retinal degenerations: hereditary • mutations