Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan
Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan
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DOI：
10.1007/s00415-021-10467-z
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发表时间：
2021-02-24
影响因子：
6
通讯作者：
Kusunoki, Susumu
中科院分区：
文献类型：
--
作者：
Inada, Rino;Hirano, Makito;Kusunoki, Susumu
背景我们旨在阐明日本脊髓小脑共济失调 2 型 (SCA2) 的表型和分子多样性。方法提取436例患者外周血DNA，其中慢性神经病患者126例，肌萎缩侧索硬化症患者108例，小脑性共济失调患者202例。然后我们对 ATXN2 基因进行 PCR 扩增和测序。对突变阳性患者的腓肠神经进行活检并进行光学显微镜和电子显微镜分析。使用雪旺细胞系 IMS32 进行转染分析。结果我们发现 PCR 扩增产物可能与四名患者的扩展 CAG 重复相对应。慢性神经病组中有两名患者进行了完全重复扩张或中间扩张（39 或 32 次重复），但没有肢体共济失调。两名患者的腓肠神经活检结果包括轴突神经病变和混合性神经病变（轴突改变伴脱髓鞘）。电子显微镜检查显示雪旺细胞具有细胞质或核内含物。两名患者最近均出现锥体征。在小脑共济失调组的第三名患者中，我们在 22 个 CAG 重复序列附近发现了一个新的 21 碱基重复突变 (c.432_452dup)。转染研究表明，21 个碱基重复的突变体 Ataxin-2 蛋白在 IMS32 中聚集，使细胞容易受到氧化应激的影响，类似于 CAG 扩增的突变体。第四名患者，重复 41 次，出现共济失调和痉挛。两名小脑性共济失调患者还患有周围神经病变。结论 CAG 重复序列扩大的患者可能表现出以前未描述过的神经病变显性表型。新的 21 个碱基重复突变体似乎具有聚谷氨酰胺扩增突变体的聚集特性。
Background We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan. Methods DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32. Results We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy. Conclusions Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants.