Gene identification for retinitis pigmentosa

Hereditary retinopathies represent the major cause of adult genetic blindness in the western world. Retinitis pigmentosa (RP) is a heterogeneous group of retinal dystrophies with a prevalence of 1:3000 and with different possible modes of inheritance. Therein, autosomal recessive RP (arRP) is the most frequent form. Today, the etiology and pathomechanism of the disease remain unknown in 85-90% of cases. Although causative mutations for arRP have been reported in about ten different human genes, these explain only a minority (< 15 %) of arRP cases. We identified a novel gene locus for arRP by localizing the disease gene in three large consanguineous families segregating arRP to chromosome 14q by use of the "homozygosity mapping" approach and by use of DNA-Chip technology. We aim to identify the disease gene and the mutation(s) in these families. Subsequently, a mutation analysis in a panel of unrelated arRP patients will be conducted to elucidate the contribution of this disease locus to all arRP cases. The identification of the disease gene in these families and the identification of disease-associated mutations in patients will contribute to the understanding of the etiology and pathomechanism of this disabling condition.

An international collaboration showed that loss of enzymatic activity of "retinol-dehydrogenase 12" causes degeneration of the retina and blindness (a form of retinitis pigmentosa, RP) in man. This disease is autosomal recessively inherited, i.e. both parents of an affected individual carry a disease-related mutation, and affected persons have inherited the mutation from both parents. Among more than 1000 investigated individuals with RP, 1.5% had mutations in the RDH12 gene, which encodes the enzyme retinol-dehydrogenase 12 (RDH12). It was shown that RDH12 plays an important role in the retinal vitamin-A metabolism and this role could be characterized in detail. Gene therapy and vitamin A supplementation studies of animals with distinct retinal vitamin A metabolism disorders give rise to speculations that persons with such mutations may be candidates for such a kind of intervention.