CHAPTER 10 Autosomal Dominant Retinitis Pigmentosa: Molecular, Genetic and Clinical Aspects PETER HUMPHRIES, GWYNETH JANE FARRAR and PAUL KENNA Department of Genetics, Trinity College Dublin 2, Ireland CONTENTS 1. Introduction ........................................................................ 231 2. Localization of the First adRP Gene to Chromosome 3 ................................... 232 3. Mutations of the Rhodopsin Gene in adRP .............................................. 235 4. Genetic Heterogeneity in adRP ......................................................... 238 5. Peripherin-RDS Mutations in adRP .................................................... 239 6. Significance of Rhodopsin and Peripherin Mutations in adRP ............................. 239 7. Clinical Findings Associated with Rhodopsin and Peripherin Mutations in adRP ............. 240 8. Conclusions ......................................................................... 243 Acknowledgements ...................................................................... 243 References ............................................................................. 243 1. INTRODUCTION Retinitis pigmentosa (RP) is the most prevalent hereditary retinopathy of man, currently estimated to affect up to 1.5 million people (for clinical reviews see Heckenlively et al., 1988 and Pagon, 1989). While approximately fifty percent of cases occur sporadically, the disease may also segregate in an autosomal dominant, an auto- somal recessive, or an X-linked fashion, although the prevalence of these genetic forms varies considerably between populations (Amman et al., 1965; Boughman and Fishman, 1983; Fishman, 1978; Jay, 1982). For a detailed review of mole- cular genetic data indicating the presence of two loci for X-linked RP (RP2 and RP3) and a locus for Usher Syndrome Type II on chromosome 1, see Humphries et al., (1990). As yet neither X-linked nor the User Syndrome Type II gene have been characterized. However, close linkage between an autosomal dominant form of the Progress in Retinal Research Vol. 12 © 1993 Pergamon Press Ltd Printed in Great Britain. 231 disease and the genetic marker C17 (D3S47) has recently been established (Farrar et al., 1989; McWilliam et al., 1989). C17 was demonstrated to lie close to the locus for rhodopsin (Farrar et al., 1990), and a mutation within that gene, a proline- for-histidine substitution at codon twenty three of exon 1, was subsequently identified in a pedigree segregating adRP (Dryja et al., 1990). Appro- ximately forty mutations within the rhodopsin gene have now been described in cases of auto- somal dominant RP (adRP). The bulk of these are single amino acid substitutions, although a number of small deletions and at least two frame- shift mutations radically altering the sequence at the carboxy-terminus of the protein have been described. More recently, two additional loci for adRP have been identified. One (Blanton et al., 1991) lies in the pericentric region of chromosome 8 (no known candidate gene resides in this region of the genome). The other lies on the proximal short arm of chromosome six close to HLA