AUTOSOMAL-DOMINANT RETINITIS-PIGMENTOSA IN A LARGE FAMILY - A CLINICAL AND MOLECULAR-GENETIC STUDY

Purpose. To characterize the pedigree, visual function phenotype, and responsible mutation in a large family with autosomal dominant retinit is pigmentosa. Methods. Pedigree data were obtained by personal interv iews and corroborated with community records. One hundred twenty-eight members of the family were examined clinically, and a subset of 12 af fected subjects was further studied with dark- and light-adapted stati c perimetry and electroretinography. The coding region of the rhodopsi n gene was polymerase chain reaction (PCR) amplified and resolved by d enaturing gradient gel electrophoresis. Genomic DNA samples from nine affected and five unaffected family members were analyzed by PCR ampli fication and restriction enzyme digestion. Results. A 14-generation pe digree was identified in which retinitis pigmentosa (RP) was inherited in an autosomal dominant fashion. Affected individuals reported early night blindness and showed vessel attenuation and bone spicule-like p igmentary changes. In these individuals, the rod electroretinogram (ER G) was not detectable, and the cone ERG was reduced in amplitude and d elayed in timing. With dark-adapted perimetry, rod function could be d etected in only one young patient, and it was markedly abnormal. Light -adapted perimetry indicated that cone sensitivity could be relatively well preserved in the central field, but it was diminished in the per iphery even in the most mildly affected subjects. A valine(345)-to-leu cine mutation was identified in the rhodopsin gene and shown to cosegr egate in the heterozygous condition with the disease. Conclusions. The natural history of RP in this family begins with a loss of rod functi on, progresses to involve the cone system, and leads eventually to a s evere loss of visual function. The invariance of valine(345) in all fu nctional vertebrate visual pigments sequenced to date, and the unusual ly conservative nature of the valine(345)-to-leucine mutation suggests that the carboxy terminus of rhodopsin is involved in a highly specif ic interaction with one or more rod proteins.