An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5′-untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains
An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5′-untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains
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DOI：
10.1086/432518
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发表时间：
2005-08-01
影响因子：
9.8
通讯作者：
Mizusawa, H
中科院分区：
文献类型：
--
作者：
Ishikawa, K;Toru, S;Mizusawa, H
常染色体显性遗传性小脑共济失调（ADCA）是一组异质性神经退行性疾病。通过定位克隆，我们已经确定了与一种退行性共济失调（染色体16q22.1连锁ADCA）密切相关的基因，该基因在临床上表现为进行性纯小脑共济失调。详细的听力图检查提示感音神经性听力障碍可能与共济失调有关。在通过单倍型分析限制染色体16q22.1中的候选区域后，我们发现来自52个无关的日本家庭的所有患者都具有杂合的C -> T单核苷酸取代，在假定蛋白DKFZP 434 I216的基因的假定翻译起始位点上游16 nt处，我们将其称为“puratrophin-1”（浦肯野细胞萎缩相关蛋白-1）。全长puratrophin-1 mRNA具有3，576 nt的开放阅读框，预测包含重要结构域，包括血影蛋白重复序列和Rho GTP酶的鸟嘌呤核苷酸交换因子（GEF），随后是Dbl同源结构域，其指示puratrophin-1在高尔基体的细胞内信号传导和肌动蛋白动力学中的作用。Puratrophin-1-通常在广泛的细胞中表达，包括耳蜗中的上皮毛细胞-聚集在染色体16q22.1连锁的ADCA大脑的浦肯野细胞中。与puratrophin-1的蛋白质预测数据一致，高尔基体膜蛋白和血影蛋白也在浦肯野细胞中形成聚集体。本研究强调了5'非翻译区（UTR）在鉴定人类疾病基因中的重要性，表明5'非翻译区中的单核苷酸取代可能与蛋白质聚集相关，并表明GEF蛋白与人类小脑变性相关。
Autosomal dominant cerebellar ataxia ( ADCA) is a group of heterogeneous neurodegenerative disorders. By positional cloning, we have identified the gene strongly associated with a form of degenerative ataxia ( chromosome 16q22.1-linked ADCA) that clinically shows progressive pure cerebellar ataxia. Detailed examination by use of audiogram suggested that sensorineural hearing impairment may be associated with ataxia in our families. After restricting the candidate region in chromosome 16q22.1 by haplotype analysis, we found that all patients from 52 unrelated Japanese families harbor a heterozygous C -> T single-nucleotide substitution, 16 nt upstream of the putative translation initiation site of the gene for a hypothetical protein DKFZP434I216, which we have called "puratrophin-1" ( Purkinje cell atrophy associated protein-1). The full-length puratrophin-1 mRNA had an open reading frame of 3,576 nt, predicted to contain important domains, including the spectrin repeat and the guanine-nucleotide exchange factor (GEF) for Rho GTPases, followed by the Dbl-homologous domain, which indicates the role of puratrophin-1 in intracellular signaling and actin dynamics at the Golgi apparatus. Puratrophin-1- normally expressed in a wide range of cells, including epithelial hair cells in the cochlea - was aggregated in Purkinje cells of the chromosome 16q22.1 - linked ADCA brains. Consistent with the protein prediction data of puratrophin-1, the Golgi-apparatus membrane protein and spectrin also formed aggregates in Purkinje cells. The present study highlights the importance of the 5' untranslated region ( UTR) in identification of genes of human disease, suggests that a single-nucleotide substitution in the 5' UTR could be associated with protein aggregation, and indicates that the GEF protein is associated with cerebellar degeneration in humans.