title: Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa.
abstract: Retinitis pigmentosa (RP), the commonest form of inherited retinal dystrophies is a clinically and genetically heterogeneous disorder. It is characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of peripheral visual field. RP is inherited either in an autosomal dominant, autosomal recessive or X-linked mode. A locus (RP18) for autosomal dominant RP was previously mapped by linkage analysis in two large pedigrees to chromosome 1p13-q21. The human HPRP3 gene, the orthologue of the yeast pre-mRNA splicing factor (PRP3), localizes within the RP18 disease interval. The recent identification of mutations in human splicing factors, PRPF31 and PRPC8, led us to screen HPRP3 as a candidate in three chromosome 1q-linked families. So far, two different missense mutations in two English, a Danish family and in three RP individuals have been identified. Both mutations are clustered within a two-codon stretch in the 11th exon of the HPRP3 gene. Interestingly, one of the mutations (T494M) is seen repeatedly in apparently unlinked families raising the possibility of a mutation hot spot. This has been confirmed by haplotype analysis using SNPs spanning the HPRP3 gene region supporting multiple origins of the mutation. The altered HPRP3 amino acids, which are highly conserved in all known HPRP3 orthologues, indicate a major function of that domain in the splicing process. The identification of mutations in a third pre-mRNA splicing factor gene further highlights a novel mechanism of photoreceptor degeneration due to defects in the splicing process.
authors.affiliation: Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EV, UK.
authors.forename: Christina F
authors.initials: CF
authors.lastname: Chakarova
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hims
authors.forename: Hanno
authors.initials: H
authors.lastname: Bolz
authors.forename: Leen
authors.initials: L
authors.lastname: Abu-Safieh
authors.forename: Reshma J
authors.initials: RJ
authors.lastname: Patel
authors.forename: Myrto G
authors.initials: MG
authors.lastname: Papaioannou
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.forename: T Jeffrey
authors.initials: TJ
authors.lastname: Keen
authors.forename: Catherine
authors.initials: C
authors.lastname: Willis
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.forename: Alan C
authors.initials: AC
authors.lastname: Bird
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
authors.forename: David
authors.initials: D
authors.lastname: Hunt
authors.forename: Eranga N
authors.initials: EN
authors.lastname: Vithana
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
mesh_terms: D000595:Amino Acid Sequence; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005799:Genes, Dominant; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D012160:Retina / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014960:X Chromosome / Q000235:genetics
chemical_list: D017931:DNA Primers; D009687:Nuclear Proteins; C108507:PRPF3 protein, human; D017414:Ribonucleoprotein, U4-U6 Small Nuclear