Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa

被引:73
作者
Bowne, SJ
Daiger, SP
Hims, MM
Sohocki, MM
Malone, KA
McKie, AB
Heckenlively, JR
Birch, DG
Inglehearn, CF
Bhattacharya, SS
Bird, A
Sullivan, LS
机构
[1] Univ Texas, Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77225 USA
[2] Univ Texas, Hlth Sci Ctr, Dept Ophthalmol & Visual Sci, Houston, TX 77225 USA
[3] Univ Leeds, Mol Med Unit, Leeds, W Yorkshire, England
[4] Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA
[5] Retina Fdn SW, Dallas, TX USA
[6] UCL, Dept Mol Genet, Inst Ophthalmol, London, England
基金
英国惠康基金;
关键词
D O I
10.1093/hmg/8.11.2121
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Retinitis pigmentosa is a genetically heterogeneous form of retinal degeneration that affects similar to 1 in 3500 people worldwide. Recently we identified the gene responsible for the RP1 form of autosomal dominant retinitis pigmentosa (adRP) at 8q11-12 and found two different nonsense mutations in three families previously mapped to 8q, The RP1 gene is an unusually large protein, 2156 amino acids in length, but is comprised of four exons only. To determine the frequency and range of mutations in RP1 we screened probands from 56 large adRP families far mutations in the entire gene. After preliminary results indicated that mutations seem to cluster in a 442 nucleotide segment of exon 4, an additional 194 probands with adRP and 409 probands with other degenerative retinal diseases were tested for mutations in this region alone. We identified eight different disease-causing mutations in 17 of the 250 adRP probands tested, All of these mutations are either nonsense or frameshift mutations and lead to a severely truncated protein. Two of the eight different mutations, Arg677X and a 5 bp deletion of nucleotides 2280-2284, were reported previously, while the remaining six mutations are novel. We also identified two rare missense changes in two other families, one new polymorphic amino acid substitution, one silent substitution and a rare variant in the 5'-untranslated region that is not associated with disease. Based on this study, mutations in RP1 appear to cause at least 7% (17/250) of adRP, The 5 bp deletion of nucleotides 2280-2284 and the Arg677X nonsense mutation account for 59% (10/17) of these mutations. Further studies will determine whether missense changes in the RP1 gene are associated with disease, whether mutations in other regions of RP1 can cause forms of retinal disease other than adRP and whether the background variation in either the mutated or wild-type RP1 allele plays a role in the disease phenotype.
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收藏
页码:2121 / 2128
页数:8
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