Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease)
Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease)
复制标题
DOI：
10.1093/hmg/7.9.1517
复制
发表时间：
1998-09-01
影响因子：
3.5
通讯作者：
Weber, BHF
中科院分区：
文献类型：
--
作者：
Marquardt, A;Stöhr, H;Weber, BHF
卵黄状黄斑营养不良（贝斯特病）是一种常染色体显性的早发性黄斑变性，其中原发性缺陷被认为发生在视网膜色素上皮水平。遗传连锁已经将疾病位点定位到染色体11 q12-q13.1，在980 kb的间隔内，两侧是位点D11 S4076和子宫珠蛋白的标记。为了鉴定疾病基因，我们系统地表征了关键区域内的基因，并分析了来自多代Best病大家族的12名患者的突变编码区。按照这种方法，我们鉴定了一种在所有12名先证者中携带杂合突变的未知功能的新基因，其中，10导致在整个进化过程中高度保守的氨基酸的不同错义突变，跨越从秀丽隐杆线虫到人的系统发育距离，并且包括V9 M、A10 T、W24 C、R25 Q、R218 Q、Y227 N、Y227 C、V235 M、P297 A和F305 S，在两个家系中发现一个缺失突变，Delta I295，并且在两种情况下与疾病分离，北方印迹分析揭示该基因的组织特异性表达，仅在视网膜色素上皮中。总之，我们的数据提供了我们已经鉴定的基因突变导致Best病的强有力证据。
Vitelliform macular dystrophy (Best's disease) is an autosomal dominant, early-onset form of macular degeneration in which the primary defect is thought to occur at the level of the retinal pigment epithelium. Genetic linkage has mapped the disease locus to chromosome 11q12-q13.1 within a 980 kb interval flanked by markers at loci D11S4076 and uteroglobin. To identify the disease gene, we systematically characterized genes from within the critical region and analysed the coding regions for mutations in 12 patients from large multigeneration Best's disease families, Following this approach, we identified a novel gene of unknown function carrying heterozygous mutations in all 12 probands, Of these, 10 result in distinct missense mutations of amino acids that are highly conserved throughout evolution, spanning a phylogenetic distance from Caenorhabditis elegans to human, and include V9M, A10T, W24C, R25Q, R218Q, Y227N, Y227C, V235M, P297A and F305S, One deletion mutation, Delta I295, was found in two families and segregates with the disease in both cases, Northern blot analysis reveals tissue-specific expression for this gene, exclusively in the retinal pigment epithelium, In conclusion, our data provide strong evidence that mutations in the gene that we have identified cause Best's disease.