The expanding roles of ABCA4 and CRB1 in inherited blindness

Mutations in the ABCA4 gene cause Stargardt disease (STGD), most cases with autosomal recessive (ar) cone-rod dystrophy (CRD), and some cases with atypical ar retinitis pigmentosa (arRP). We found compound heterozygous ABCA4 mutations in two unrelated patients with STGD and homozygous splice site mutations in their 2nd and 4th degree cousins with RP. Some ABCA4 mutations display strong founder effects. In Dutch and German STGD patients, the 768G > T mutation is present in 8% and 0.6% of ABCA4 alleles respectively. Vice versa, the complex L541P;A1038V allele is found in 70% of ABCA4 alleles in German STGD patients but absent in Dutch patients. As approximately 70% of ABCA4 mutations are known, a microarray-based analysis of known ABCA4 gene variants allows routine DNA diagnostics in Caucasian patients. Mutations in the CRB1 gene underlie RP12, some cases with classic arRP, 55% of cases with RP and Coats-like exudative vasculopathy, and 13% of patients with Leber congenital amaurosis (LCA), rendering CRB1 a significant cause of autosomal recessive retinal dystrophy. Different combinations of mutations in ABCA4 or CRB1 can be correlated with disease severity, suggesting that small increments of protein activities in patients might have significant therapeutic effects. Mouse and Drosophila studies strongly suggest that both patient groups might benefit from reduced light exposure and therefore should be detected as early as possible using molecular techniques.