von Brederlow Benigna, Bolz Hanno, Janecke Andreas, La O Cabrera Alicia, Rudolph Günther, Lorenz Birgit, Schwinger Eberhard, Gal Andreas
Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Hum Mutat. 2002 Mar;19(3):268-73. doi: 10.1002/humu.10049.
Usher syndrome (USH) is a group of autosomal recessive sensory disorders characterized by progressive retinitis pigmentosa (RP) and sensorineural hearing impairment. Usher syndrome type 1 (USH1), with additional vestibular dysfunction, represents the most severe form and shows extensive allelic and non-allelic heterogeneity. At least six USH1 loci exist (USH1A-F), and four of the underlying genes have been identified. Recently, a novel gene, cadherin 23 (CDH23), was shown to be mutated in USH1D. We performed mutation screening by single strand conformation polymorphism (SSCP) analysis and direct sequencing on 33 USH1 patients previously excluded for USH1B and USH1C. On eight disease alleles of four patients, four different mutations were identified, three of them novel (c.6933delT, c.5712G-->A, and IVS45-9G-->A). Exon trapping experiments were performed with two mutations. In the case of a c.5712G-->A transition of the last base of exon 42, that is an apparently synonymous mutation, skipping of exon 42 was observed. By the mutation IVS45-9G-->A, a novel splice acceptor site was created and the insertion of 7 intronic bp was observed. Two mutations, IVS45-9G-->A and the previously described IVS51+5G-->A, were each found in more than one patient. Haplotype analysis by SNPs within CDH23 suggests common ancestors for each of the mutations. Among the total of 52 USH1 cases studied by us, CDH23 mutations account for about 10% of all disease alleles. Our results further suggest that in patients with a typical USH1D phenotype, a significant portion of CDH23 mutations leads to premature termination of translation or loss of numerous amino acid residues, with a high frequency of changes causing aberrant splicing of CDH23 mRNA.
尤塞综合征（USH）是一组常染色体隐性遗传性感觉障碍疾病，其特征为进行性视网膜色素变性（RP）和感音神经性听力障碍。1型尤塞综合征（USH1）伴有额外的前庭功能障碍，是最严重的一种类型，表现出广泛的等位基因和非等位基因异质性。至少存在六个USH1基因座（USH1A - F），并且已经鉴定出其中四个相关基因。最近，一种新基因，钙黏蛋白23（CDH23），被证明在USH1D中发生突变。我们通过单链构象多态性（SSCP）分析和直接测序对33例先前排除了USH1B和USH1C的USH1患者进行了突变筛查。在四名患者的八个疾病等位基因上，鉴定出四个不同的突变，其中三个是新突变（c.6933delT、c.5712G→A和IVS45 - 9G→A）。对两个突变进行了外显子捕获实验。对于外显子42最后一个碱基的c.5712G→A转换，这是一个明显的同义突变，观察到外显子42跳跃。通过IVS45 - 9G→A突变，产生了一个新的剪接受体位点，并观察到7个内含子碱基的插入。IVS45 - 9G→A和先前描述的IVS51 + 5G→A这两个突变均在不止一名患者中发现。通过CDH23内的单核苷酸多态性（SNP）进行单倍型分析表明每个突变都有共同的祖先。在我们研究的总共52例USH1病例中，CDH23突变约占所有疾病等位基因的10%。我们的结果进一步表明，在具有典型USH1D表型的患者中，很大一部分CDH23突变导致翻译提前终止或大量氨基酸残基缺失，并且高频变化导致CDH23 mRNA异常剪接。
