Retinitis Pigmentosa 13
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-13 (RP13) is caused by heterozygous mutation in the PRPF8 gene (607300) on chromosome 17p13.
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Clinical FeaturesThe family with autosomal dominant retinitis pigmentosa (adRP) studied by Greenberg et al. (1994) was of British stock. The great-grandfather came to South Africa from Suffolk, England, in the mid-1800s. The onset of night blindness was between 4 and 10 years of age. By middle age, some patients had diffuse fundal changes and extensive retinal degeneration. The changes were classic midequatorial pigmentation and constricted visual fields at an early age in many patients. The presentation was considered to be that of early-onset adRP with diffuse retinal involvement, i.e., type I(D).
Maubaret et al. (2011) reported detailed genotype/phenotype correlation in 2 British autosomal dominant retinitis pigmentosa families with mutations in the PRPF8 gene. All affected members complained of nyctalopia with variable age of onset. In the first family, there was marked phenotypic variation, from severe rod-cone dystrophy to normal retinal appearance and mild rod dysfunction on scotopic electroretinography in a 67-year-old patient. The second family demonstrated similar variability and included a nonpenetrant individual.
MappingGreenberg et al. (1994) provided definitive evidence for the localization of a gene for adRP, here symbolized RP13, on 17p by linkage analysis in a large South African kindred. The recoverin gene (RCV1; 179618) is located at 17p13.1. Although it was considered a prime candidate for adRP in the family studied, mutation screening of the 3 exons of this gene failed to reveal any mutation. Furthermore, Goliath et al. (1995) excluded linkage to the RCV1 gene because of recombination observed with an intragenic RCV1 marker described by Wiechmann et al. (1994).
By further studies in the South African family originally described by Greenberg et al. (1994), Goliath et al. (1995) refined the localization of the RP13 gene in 17p13.1 to the interval between D17S1529 and D17S831. In a large 8-generation family of British descent living in the United States, Kojis et al. (1996) mapped the gene to the 17p13.3 region. Reanalysis of the South African family, in conjunction with the American data, suggested that only one autosomal dominant RP locus exists on 17p but that it maps to 17p13.3, a more telomeric position than previously reported. In an affected 3-generation family originating from South Cumbria, England, Tarttelin et al. (1996) confirmed the refinement data of Goliath et al. (1995).
Molecular GeneticsUsing a positional cloning and candidate gene strategy, McKie et al. (2001) identified 7 different missense mutations in the PRPF8 splicing factor gene (607300) in autosomal dominant RP families. Three of the mutations cosegregated within 3 RP13 linked families, including the original large South African pedigree, and 4 additional mutations had been identified in other unrelated autosomal dominant RP families. The 7 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 exhibited a high degree of conservation across species as diverse as humans, Arabidopsis, and trypanosome, suggesting that some functional significance may be associated with this part of the protein.
Maubaret et al. (2011) reported mutations in the PRPF8 gene in 2 British families with autosomal dominant retinitis pigmentosa, one of which had been reported by Towns et al. (2010). Maubaret et al. (2011) concluded that theirs was the first report of marked intrafamilial variability, including incomplete penetrance, associated with mutations in the PRPF8 gene. Maubaret et al. (2011) suggested that PRPF8 mutations should be suspected in patients with autosomal dominant retinitis pigmentosa and variable expressivity.