Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan.
Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan.
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DOI：
10.1007/s10048-010-0245-6
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发表时间：
2010-10
期刊：
影响因子：
2.2
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
--
作者：
Sakai, Haruya;Yoshida, Kunihiro;Shimizu, Yusaku;Morita, Hiroshi;Ikeda, Shu-ichi;Matsumoto, Naomichi
脊髓小脑型共济失调31型(SCA31)是常染色体显性遗传性小脑性共济失调(ADCA)的一种新亚型，以成人起病的纯性小脑性共济失调为特征。白藜芦醇-1基因(PLEKHG4)5‘非翻译区的C/T替换或PLEKHG4上游的900kb SCA31关键区内的疾病特异性单倍型已被用于诊断SCA31。最近，在SCA31患者的这个关键区域发现了一个包含五核苷酸(TGGAA)n重复的疾病特异性插入。SCA31在日本长野非常流行，在那里SCA31约占ADCA家庭的42%。我们对长野71个家庭的94名SCA31患者进行了插入筛查。所有患者都有2.6-3.7kb的插入。附着点的大小与发病年龄呈负相关，但与发病后的进展率无关。插入片段5‘端的(TAGAA)n重复序列数目可变，范围为0(不含TAGAA序列)到4。(TAGAA)n重复序列的数目与插入片段的总大小呈负相关。来自长野三个疫源地的患者中，(TAGAA)n重复序列的数量相对一致。仅有1例PLEKHG4基因C/T杂合子患者同时存在两个等位基因的插入，大小分别约为3.0和4.3kb。用生物素标记的(TGGAA)5探针测序和Southern杂交表明，3.0kb的插入片段，而不是4.3kb的插入片段，含有(TGGAA)n拉伸。我们还发现，在405个对照个体中，有3个(0.7%)的插入片段长度在1.0-3.5kb之间。在PLEKHG4中C/T替换均为阴性，测序结果均未发现含有(TGGAA)n的插入片段在其5‘端伸展。用(TAAAA)5探针Southern杂交可清楚地检测到正常对照的插入片段，而(TGGAA)5或(TAGAA)5探针未标记。这些数据表明，对照等位基因很少在SCA31关键区域有非致病的大插入，不仅插入的存在，而且其大小都不足以证明是致病等位基因。我们同意(TGGAA)n重复插入确实与SCA31的发病有关的观点，但尚不能确定缺少(TGGAA)n的大插入是否是非致病的。
Spinocerebellar ataxia type 31 (SCA31) is a recently defined subtype of autosomal dominant cerebellar ataxia (ADCA) characterized by adult-onset, pure cerebellar ataxia. The C/T substitution in the 5′-untranslated region of the puratrophin-1 gene (PLEKHG4) or a disease-specific haplotype within the 900-kb SCA31 critical region just upstream of PLEKHG4 has been used for the diagnosis of SCA31. Very recently, a disease-specific insertion containing penta-nucleotide (TGGAA)n repeats has been found in this critical region in SCA31 patients. SCA31 was highly prevalent in Nagano, Japan, where SCA31 accounts for approximately 42% of ADCA families. We screened the insertion in 94 SCA31 patients from 71 families in Nagano. All patients had a 2.6- to 3.7-kb insertion. The size of the insertion was inversely correlated with the age at onset but not associated with the progression rate after onset. (TAGAA)n repeats at the 5′-end of the insertion were variable in number, ranging from 0 (without TAGAA sequence) to 4. The number of (TAGAA)n repeats was inversely correlated to the total size of the insertion. The number of (TAGAA)n repeats was comparatively uniform within patients from the three endemic foci in Nagano. Only one patient, heterozygous for the C/T substitution in PLEKHG4, had the insertions in both alleles; they were approximately 3.0 and 4.3 kb in size. Sequencing and Southern hybridization using biotin-labeled (TGGAA)5 probe strongly indicated that the 3.0-kb insertion, but not the 4.3-kb insertion, contained (TGGAA)n stretch. We also found that 3 of 405 control individuals (0.7%) had the insertions from 1.0 to 3.5 kb in length. They were negative for the C/T substitution in PLEKHG4, and neither of the insertions contained (TGGAA)n stretch at their 5′-end by sequencing. The insertions in normal controls were clearly detected by Southern hybridization using (TAAAA)5 probe, while they were not labeled with (TGGAA)5 or (TAGAA)5 probe. These data indicate that control alleles very rarely have a nonpathogenic large insertion in the SCA31 critical region and that not only the presence of the insertion but also its size is not sufficient evidence for a disease-causing allele. We approve of the view that (TGGAA)n repeats in the insertion are indeed related to the pathogenesis of SCA31, but it remains undetermined whether a large insertion lacking (TGGAA)n is nonpathogenic.
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