Human Molecular Genetics, 2001, Vol. 10, No. 15 1555-1562
© 2001 Oxford University Press
Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13)
Molecular Medicine Unit, University of Leeds, Clinical Sciences Building, St James’ University Hospital, Leeds LS9 7TF, UK, 1Section of Molecular Genetics, Division of Biomedical Sciences, Imperial College School of Medicine, London SW7 4AY, UK, 2Department of Human Genetics, University of Cape Town Medical School, Cape Town, South Africa, 3Department of Ophthalmology and 4Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, The Netherlands, 5CERA, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia and 6Department of Molecular Genetics, Institute of Ophthalmology, University College London, London EC1V 9EL, UK
Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of visual fields. With an incidence of approximately 1 in 4000, RP can be inherited in X-linked, autosomal dominant or autosomal recessive modes. The RP13 locus for autosomal dominant RP (adRP) was placed on chromosome 17p13.3 by linkage mapping in a large South African adRP family. Using a positional cloning and candidate gene strategy, we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families. Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree, and four additional mutations have been identified in other unrelated adRP families. The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript. The altered amino acid residues at the C-terminus exhibit a high degree of conservation across species as diverse as humans, Arabidopsis and trypanosome, suggesting that some functional significance is associated with this part of the protein. These mutations in this ubiquitous and highly conserved splicing factor offer compelling evidence for a novel pathway to retinal degeneration.
+ To whom correspondence should be addressed. Tel: +44 113 206 5698; Fax: +44 113 244 4475; Email: cinglehe@hgmp.mrc.ac.ukThe authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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