Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1
Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1
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DOI：
10.1086/302609
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发表时间：
1999-11-01
影响因子：
9.8
通讯作者：
Barrett, T
中科院分区：
文献类型：
--
作者：
Hardy, C;Khanim, F;Barrett, T
Wolfram综合征是一种常染色体隐性遗传的神经退行性疾病，以青少年发病的糖尿病和进行性视神经萎缩为特征。线粒体DNA缺失已被描述，最近在染色体4p 16上鉴定了一个基因（WFS 1），编码一个预测的830个氨基酸的跨膜蛋白。对19例英国脑卒中患者的30例WFS 1基因进行了直接DNA测序，以筛选其整个编码区。还筛查了DNA中的结构重排（缺失和重复）和mtDNA中的点突变。在我们的队列中未发现致病性mtDNA突变。我们在WFS 1基因中发现了24个突变：8个无义突变，8个错义突变，3个框内缺失，1个框内插入和4个移码突变。其中，23个是新的突变，大多数发生在外显子8。大多数患者为两个突变的复合杂合子，没有共同的创始者突变。还分析了基因型-表型关系的数据。虽然注意到一些有趣的病例，但考虑到小样本量和每个突变的频率，表明任何观察到的突变与疾病严重程度之间没有明确的相关性。没有明显的突变热点或突变簇。因此，分子筛选Wolfram综合征在受影响的家庭和Wolfram综合征携带状态的精神疾病或糖尿病患者将需要完整的分析外显子8和上游外显子。
Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and progressive optic atrophy. mtDNA deletions have been described, and a gene (WFS1) recently has been identified, on chromosome 4p16, encoding a predicted 830 amino acid transmembrane protein. Direct DNA sequencing was done to screen the entire coding region of the WFS1 gene in 30 patients from 19 British kindreds with Wolfram syndrome. DNA was also screened for structural rearrangements (deletions and duplications) and point mutations in mtDNA. No pathogenic mtDNA mutations were found in our cohort. We identified 24 mutations in the WFS1 gene: 8 nonsense mutations, 8 missense mutations, 3 in-frame deletions, 1 in-frame insertion, and 4 frameshift mutations. Of these, 23 were novel mutations, and most occurred in exon 8. The majority of patients were compound heterozygotes for two mutations, and there was no common founder mutation. The data were also analyzed for genotype-phenotype relationships. Although some interesting cases were noted, consideration of the small sample size and frequency of each mutation indicated no clear-cut correlations between any of the observed mutations and disease severity. There were no obvious mutation hot spots or clusters. Hence, molecular screening for Wolfram syndrome in affected families and for Wolfram syndrome-carrier status in subjects with psychiatric disorders or diabetes mellitus will require complete analysis of exon 8 and upstream exons.