[Genetics of retinitis pigmentosa: metabolic classification and phenotype/genotype correlations]

Abstract

Retinitis pigmentosa (RP, prevalence 1/4000) is a set of hereditary retinal dystrophies characterized by pigment deposits in fundus and progressive death of photoreceptors, always associated with the alteration of retinal pigment epithelium. Genetic heterogeneity of the typical nonsyndromic form (rod cone dystrophy) is extensive: 11 genes and one locus were reported for autosomal dominant RP, 17 genes and five loci for autosomal recessive RP, and two genes and two loci for X-linked RP. A survey of mutation screening reports in large series of patients indicates that the frequency of mutations for all cloned genes varies from 40% to 54% of cases in autosomal dominant RP, from 17% to 24% in autosomal recessive RP (excluding the USH2A gene for which the values remain uncertain) and from 61% to 89% in X-linked RP. Very few studies report on sporadic cases except for the two X-linked genes, RP2 and RPGR, which account for 29% of sporadic cases in males. Altogether, the two most frequently involved genes are RPGR (13% of all RP cases) and RHO (4%), an important consideration for molecular diagnosis. Finally, we roughly estimate that currently known genes do not represent more than 50% of RP cases, suggesting that many genes remain to be discovered. The known genes can be classified into metabolic groups according to the encoded protein: visual transduction, visual cycle, transcription factors, structural proteins, spliceosome complex and cellular traffic, indicating the high level of specialization of photoreceptors and of the retinal pigment epithelium. In parallel with this classification, genotype/phenotype correlations have been established that will help ophthalmologists to suspect particular genes, and thereby mechanisms. This approach will provide better informations to patients and will orient the choice of future therapies.