Rhodopsin mutations in inherited retinal dystrophies and dysfunctions

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Abstract

Our understanding on the molecular basis of inherited retinal dystrophies and dysfunctions has been rapidly evolving during the last couple of years following the identification of several genes implicated in these conditions. We have compiled a comprehensive list of rhodopsin gene mutations, consisting of 92 entries, identified in single patients and/or cosegregating with the disease phenotype in families with such disorders. Remarkably, this extreme genetic heterogeneity is largely simplified at the level of the gene product; in vitro expression studies suggest that most rhodopsin mutations result in one of three possible and well-defined biochemical abnormality patterns. One group of the degenerative retinopathies, retinitis pigmentosa (RP), has attracted special attention as it is the most frequent cause of genetic blindness in adulthood. It turns out that heterozygous rhodopsin mutations account for about 25% of all autosomal dominant RP cases in continental Europe, in the UK, and in the United States. Of the five rhodopsin mutations not pathogenic in the heterozygous state, two have been implicated in autosomal recessive RP in homozygotes. In order to examine the correlation between genotype (gene mutation) and phenotype (ocular findings) in autosomal dominant RP, an attempt is made to summarize and synthesize the large body of data obtained by the clinical examination of unrelated patients carrying the same rhodopsin mutation or by that of patients from individual families. Congenital stationary nightblindness (CSNB) is a clinically and genetically heterogeneous group of retinal dysfunctions. It is not accompanied by retinal dystrophy, and considered a pure functional defect. It has been suggested that in one form of CSNB mutant rhodopsin is responsible for the condition. It is intriguing that mutations of the same gene, that encoding rhodopsin, depending on their nature and location may result either in a progressive and degenerative dominant or recessive retinopathy or in a stationary pure functional deficiency. In vitro studies in cultured cells as well as the examination of transgenic animals carrying different rhodopsin mutations are important experimental tools and may help to better understand the complex mechanisms by which a given mutation triggers a pathological process.

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