Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy
Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy
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DOI：
10.1038/ng1394
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发表时间：
2004-08-01
期刊：
影响因子：
30.8
通讯作者：
Gal, A
中科院分区：
文献类型：
--
作者：
Janecke, AR;Thompson, DA;Gal, A
受常染色体隐性儿童期发病的严重视网膜营养不良影响的成员，这是一种以光感受器细胞变性为特征的遗传异质性疾病组(1)。通过单核苷酸多态性微阵列分析的全基因组扫描（参考文献2）确定了一个创始单倍型，并在染色体14q23.3-q24.1上定义了一个1.53 cM的临界间隔，该间隔包含与这种形式的视网膜营养不良相关的基因。RDH12位于该区域，并编码视黄醇脱氢酶，该酶被认为在视觉周期中起作用(3)。RDH12的纯合子677A - >g转变（导致Y226C）存在于所有受影响的家庭成员中，以及两名散发视网膜营养不良的奥地利人。我们在89名患有视网膜营养不良的非奥地利人中的3人中发现了RDH12的其他突变：5个核苷酸缺失（806delCCCTG）和565C -> T过渡（导致Q189X），每个都处于纯合状态，146C -> T（导致T49M）和184C -> T（导致R62X）处于复合杂合状态。当在COS-7细胞中表达时，Cys226和Met49变体分别在视黄醇和视网膜的互转化异构体中表现出减弱和异常的活性。RDH12突变个体的严重视力障碍与编码另一种视网膜脱氢酶的RDH5突变导致的albipunctatus个体的轻度视力缺陷形成鲜明对比(4)。我们的研究表明，RDH12与视网膜营养不良有关，并编码一种在感光细胞中具有独特，非冗余作用的酶。
members affected by autosomal recessive childhood-onset severe retinal dystrophy, a genetically heterogeneous group of disorders characterized by degeneration of the photoreceptor cells(1). A whole-genome scan by microarray analysis of single-nucleotide polymorphisms (ref. 2) identified a founder haplotype and defined a critical interval of 1.53 cM on chromosome 14q23.3-q24.1 that contains the gene associated with this form of retinal dystrophy. RDH12 maps in this region and encodes a retinol dehydrogenase proposed to function in the visual cycle(3). A homozygous 677A --> G transition (resulting in Y226C) in RDH12 was present in all affected family members studied, as well as in two Austrian individuals with sporadic retinal dystrophy. We identified additional mutations in RDH12 in 3 of 89 non-Austrian individuals with retinal dystrophy: a 5-nucleotide deletion (806delCCCTG) and the transition 565C --> T ( resulting in Q189X), each in the homozygous state, and 146C --> T (resulting in T49M) and 184C --> T (resulting in R62X) in compound heterozygosity. When expressed in COS-7 cells, Cys226 and Met49 variants had diminished and aberrant activity, respectively, in interconverting isomers of retinol and retinal. The severe visual impairment of individuals with mutations in RDH12 is in marked contrast to the mild visual deficiency in individuals with fundus albipunctatus caused by mutations in RDH5, encoding another retinal dehydrogenase(4). Our studies show that RDH12 is associated with retinal dystrophy and encodes an enzyme with a unique, nonredundant role in the photoreceptor cells.