Riazuddin S Amer, Zulfiqar Fareeha, Zhang Qingjiong, Sergeev Yuri V, Qazi Zaheeruddin A, Husnain Tayyab, Caruso Rafael, Riazuddin Sheikh, Sieving Paul A, Hejtmancik J Fielding
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
Invest Ophthalmol Vis Sci. 2005 Jul;46(7):2264-70. doi: 10.1167/iovs.04-1280.
To localize and identify the gene and mutations causing autosomal recessive retinitis pigmentosa in three consanguineous Pakistani families.
Blood samples were collected and DNA was extracted. A genome-wide scan was performed by using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and lod scores were calculated.
A genome-wide scan of 25 families gave an hlod = 4.53 with D8S260. Retinitis pigmentosa in all three families mapped to a 14.21-cM (21.19-Mb) region on chromosome 8 at q11, flanked by D8S532 and D8S260. This region harbors RP1, which is known to cause autosomal dominant retinitis pigmentosa. Sequencing of the coding exons of RP1 showed mutations in all three families: two single-base deletions, c.4703delA and c.5400delA, resulting in a frame shift, and a 4-bp insertion, c.1606insTGAA, all causing premature termination of the protein. All affected individuals in these families are homozygous for the mutations. Parents and siblings heterozygous for the mutant allele did not show any signs or symptoms of RP.
These results provide strong evidence that mutations in RP1 can result in recessive as well as dominant retinitis pigmentosa. The findings suggest that truncation of RP1 before the BIF motif or within the terminal portion results in a simple loss of RP1 function, producing a recessive inheritance pattern. In contrast, disruption of RP1 within or immediately after the BIF domain may result in a protein with a deleterious effect and hence a dominant inheritance pattern.
定位并鉴定导致三个巴基斯坦近亲家庭患常染色体隐性遗传性视网膜色素变性的基因及突变。
采集血样并提取DNA。使用382个多态性微卫星标记对患病和未患病家庭成员的基因组DNA进行全基因组扫描，并计算连锁对数。
对25个家庭进行全基因组扫描，与D8S260的连锁对数hlod = 4.53。所有三个家庭的视网膜色素变性都定位于8号染色体q11上一个14.21厘摩（21.19兆碱基）的区域，两侧分别为D8S532和D8S260。该区域包含已知会导致常染色体显性遗传性视网膜色素变性的RP1。对RP1编码外显子进行测序发现所有三个家庭都存在突变：两个单碱基缺失，即c.4703delA和c.5400delA，导致移码，以及一个4碱基插入，即c.1606insTGAA，所有这些都导致蛋白质过早终止。这些家庭中所有受影响的个体均为这些突变的纯合子。携带突变等位基因的杂合子父母和兄弟姐妹未表现出任何视网膜色素变性的体征或症状。
这些结果提供了强有力的证据，表明RP1中的突变可导致隐性和显性视网膜色素变性。研究结果表明，在BIF基序之前或末端部分截断RP1会导致RP1功能简单丧失，产生隐性遗传模式。相比之下，在BIF结构域内或之后立即破坏RP1可能会导致产生具有有害作用的蛋白质，从而产生显性遗传模式。
