Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia
Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia
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DOI：
10.1007/s10038-007-0154-1
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
Mizusawa, Hidehiro
中科院分区：
文献类型：
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作者：
Amino, Takeshi;Ishikawa, Kinya;Mizusawa, Hidehiro
16q22.1连锁常染色体显性小脑共济失调（16q-ADCA；在线孟德尔遗传在人[OMIN] #117210）是日本最常见的adca之一。在此之前，我们已经报道了患者通过奠基人效应具有共同的单倍型，并且puratrophin-1基因中的C-to-T替换（-16C > T）与该疾病密切相关。然而，最近，一个例外的病人没有替代报告，表明一个真正的致病突变可能存在于其他地方。在这项研究中，我们通过对纯种小脑性共济失调家族的单倍型分析，更明确地阐明了疾病位点。除了微卫星标记外，我们还检测了在疾病染色体上发现的单核苷酸多态性（snp），以确定疾病位点的边界。对64个具有-16C > T替换的紫脓杆菌蛋白-1基因家族的分析显示，一个家族在疾病染色体上的SNP04和SNP05之间存在祖先重组事件。对22个没有可识别基因突变的家族进行分析，发现另一个家族携带有共同的单倍型着丝粒到puratrophin-1基因，但缺乏该基因的-16C > T替代。我们得出的结论是，16q-ADCA的疾病位点肯定局限于16q22.1中puratrophin-1基因的SNP04和-16C > T替换之间的900kb基因组区域。
The 16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA; Online Mendelian Inheritance in Man [OMIN] #117210) is one of the most common ADCAs in Japan. Previously, we had reported that the patients share a common haplotype by founder effect and that a C-to-T substitution (-16C > T) in the puratrophin-1 gene was strongly associated with the disease. However, recently, an exceptional patient without the substitution was reported, indicating that a true pathogenic mutation might be present elsewhere. In this study, we clarified the disease locus more definitely by the haplotype analysis of families showing pure cerebellar ataxia. In addition to microsatellite markers, the single nucleotide polymorphisms (SNPs) that we identified on the disease chromosome were examined to confirm the borders of the disease locus. The analysis of 64 families with the -16C > T substitution in the puratrophin-1 gene revealed one family showing an ancestral recombination event between SNP04 and SNP05 on the disease chromosome. The analysis of 22 families without identifiable genetic mutations revealed another family carrying the common haplotype centromeric to the puratrophin-1 gene, but lacking the -16C > T substitution in this gene. We concluded that the disease locus of 16q-ADCA was definitely confined to a 900-kb genomic region between the SNP04 and the -16C > T substitution in the puratrophin-1 gene in 16q22.1.