Evaluation of the human arrestin gene in patients with retinitis pigmentosa and stationary night blindness.

摘要

PURPOSE: To establish the DNA sequence of the coding regions of the human arrestin locus and to determine whether defects in this sequence are present among patients with retinitis pigmentosa (RP) or types of stationary night blindness in addition to Oguchi disease. METHODS: The human genomic locus encoding arrestin was cloned in bacteriophage and P1 vectors. The sequence of the intron DNA flanking each exon was determined from these clones. Single-strand conformation polymorphism analysis and direct genomic sequencing techniques were used to screen 272 unrelated patients, comprising 177 patients with autosomal dominant RP, 85 with recessive RP, and 10 with stationary night blindness. RESULTS: The arrestin gene is divided into 16 exons ranging in size from 10 bp to 194 bp, with the open reading frame spanning exons 2 through 16. The authors identified several discrepancies between the genomic sequence the authors obtained and the previously published cDNA and genomic sequences. In the set of patients with dominant RP, the authors found one of three heterozygous missense changes (Arg84Cys, Thr125Met, and Val378Ile) in each of four unrelated patients; none of these changes cosegregated with disease in the respective families. In the set of patients with recessive RP, the authors found one of two heterozygous missense changes in each of two unrelated patients with recessive RP (Pro364Leu and Arg384Cys). One of the patients was the offspring of a consanguineous marriage; because the Arg384Cys change in him was heterozygous, it is unlikely to have been the cause of his RP. Cosegregation studies could not be performed on the patient with the Pro364Leu change. The authors confirmed the existence of two previously described polymorphisms (Ile76Val and a multiallelic polymorphism at codon 403), and the authors identified several silent polymorphisms and rare sequence variants. No sequence changes, other than polymorphic changes also found in some patients with RP, were identified in the patients with stationary night blindness. CONCLUSIONS: We found no evidence that mutations in arrestin are a cause of RP or stationary night blindness other than Oguchi disease. According to the genomic sequence obtained, a region in exon 8 that has been postulated to represent the site of interaction between arrestin and rhodopsin is 100% conserved between humans and all other mammals studied to date.