Sequence variation within the RPGR gene: evidence for a founder complex allele.
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.
Zito
I
I
Department of Molecular Genetics, Institute of Ophthalmology, UCL, London, UK.
Morris
A
A
Tyson
P
P
Winship
I
I
Sharp
D
D
Gilbert
D
D
Thiselton
D L
DL
Bhattacharya
S S
SS
Hardcastle
A J
AJ
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*
D002352:Carrier Proteins; D005136:Eye Proteins; C099929:RPGR protein, human