Mutations in IMPG2, Encoding Interphotoreceptor Matrix Proteoglycan 2, Cause Autosomal-Recessive Retinitis Pigmentosa
Mutations in IMPG2, Encoding Interphotoreceptor Matrix Proteoglycan 2, Cause Autosomal-Recessive Retinitis Pigmentosa
复制标题
DOI：
10.1016/j.ajhg.2010.07.004
复制
发表时间：
2010-08-13
影响因子：
9.8
通讯作者：
den Hollander, Anneke I.
中科院分区：
文献类型：
--
作者：
Bandah-Rozenfeld, Dikla;Collin, Rob W. J.;den Hollander, Anneke I.
视网膜色素变性是由视网膜感光细胞进行性变性引起的一组异质性遗传性视网膜疾病。利用同源作图，我们鉴定了两个家系，每个家系有三个受影响的兄弟姐妹共享大片重叠的纯合子区域，这些区域包含3号染色体上的IMPG2基因。两个索引病例的IMPG2序列分析显示，在各自的家庭中，与疾病相关的纯合子突变：三个受影响的伊拉克犹太血统的兄弟姐妹表现出无义突变，而一个荷兰家庭显示出1.8kb的基因组缺失，移除了外显子9，导致IMPG2蛋白保守的海区中缺少七个氨基酸。COS-1细胞的瞬时转染表明，表达野生型SEA结构域的构建体正确地靶向于质膜，而缺乏这7个氨基酸的突变体似乎保留在内质网中。对来自荷兰、以色列、意大利和巴基斯坦的另外10个具有IMPG2纯合区的索引病例的突变分析显示，另外5个突变；4个无义突变和1个错义突变影响高度保守的苯丙氨酸残基。大多数IMPG2基因突变的患者表现为早发性RP，进行性视野丧失和视力下降。然而，携带错义突变的患者被诊断为黄斑病变。IMPG2基因编码光感受器间基质蛋白多糖IMPG2，它是光感受器间基质的组成部分。因此，我们的数据表明，光感受器间基质的一个结构成分的突变可以引起ARRP。
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases caused by progressive degeneration of the photoreceptor cells. Using autozygosity mapping, we identified two families, each with three affected siblings sharing large overlapping homozygous regions that harbored the IMPG2 gene on chromosome 3. Sequence analysis of IMPG2 in the two index cases revealed homozygous mutations cosegregating with the disease in the respective families: three affected siblings of Iraqi Jewish ancestry displayed a nonsense mutation, and a Dutch family displayed a 1.8 kb genomic deletion that removes exon 9 and results in the absence of seven amino acids in a conserved SEA domain of the IMPG2 protein. Transient transfection of COS-1 cells showed that a construct expressing the wild-type SEA domain is properly targeted to the plasma membrane, whereas the mutant lacking the seven amino acids appears to be retained in the endoplasmic reticulum. Mutation analysis in ten additional index cases that were of Dutch, Israeli, Italian, and Pakistani origin and had homozygous regions encompassing IMPG2 revealed five additional mutations; four nonsense mutations and one missense mutation affecting a highly conserved phenylalanine residue. Most patients with IMPG2 mutations showed an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity. The patient with the missense mutation, however, was diagnosed with maculopathy. The IMPG2 gene encodes the interphotoreceptor matrix proteoglycan IMPG2, which is a constituent of the interphotoreceptor matrix. Our data therefore show that mutations in a structural component of the interphotoreceptor matrix can cause arRP.