title: Sequence variation within the RPGR gene: evidence for a founder complex allele.
abstract: In our study of sequence variation within the RPGR gene associated with X-linked retinitis pigmentosa, we and others have observed a high rate of new mutation within this gene, as all reported mutations are unique or uncommon. In this article we report the identification in a single family of a complex allele of 7 sequence variants in linkage disequilibrium, of which four result in amino-acid alterations (Arg425Lys, DGlu, Thr533Met and Gly566Glu). This complex allele was initially found in a family with XLRP. However, further study revealed an estimated prevalence of 4.3% (15/344 chromosomes) with this complex allele in the European population indicating the non-pathogenic nature of this allele and, along with previously reported polymorphisms, further supporting a high level of human protein diversity for RPGR. This common complex allele may have been established in the population as a founder effect. Complete gene sequencing identified a potential pathogenic sequence variant in the family described (IVS6+5G>A). This study emphasises the need to create a more complete picture of the allelic variation within a gene, suggests cautious interpretation of a phenotypic association with variant sequences, and highlights the potential problems associated with interpreting genetic studies for diagnostic purposes.
authors.affiliation: Department of Molecular Genetics, Institute of Ophthalmology, UCL, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Zito
authors.forename: A
authors.initials: A
authors.lastname: Morris
authors.forename: P
authors.initials: P
authors.lastname: Tyson
authors.forename: I
authors.initials: I
authors.lastname: Winship
authors.forename: D
authors.initials: D
authors.lastname: Sharp
authors.forename: D
authors.initials: D
authors.lastname: Gilbert
authors.forename: D L
authors.initials: DL
authors.lastname: Thiselton
authors.forename: S S
authors.initials: SS
authors.lastname: Bhattacharya
authors.forename: A J
authors.initials: AJ
authors.lastname: Hardcastle
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D005136:Eye Proteins; D005260:Female; D018703:Founder Effect; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; C099929:RPGR protein, human