ARSA variants in α-synucleinopathies.
ARSA variants in α-synucleinopathies.
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DOI：
10.1093/brain/awz340
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发表时间：
2019-12
期刊：
影响因子：
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通讯作者：
Mary B Makarious;M. Diez-Fairen;L. Krohn;C. Blauwendraat;S. Bandres-Ciga;Jinhui Ding;L. Pihlstrøm;H. Houlden;Sonja W. Scholz;Z. Gan-Or
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文献类型：
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作者：
Mary B Makarious;M. Diez-Fairen;L. Krohn;C. Blauwendraat;S. Bandres-Ciga;Jinhui Ding;L. Pihlstrøm;H. Houlden;Sonja W. Scholz;Z. Gan-Or
先生，我们怀着极大的兴趣阅读了Lee及其同事最近发表的报告ARSA变异及其与帕金森病相关性的文章（Lee et al.，2019年）。芳基硫酸酯酶A的缺乏是异染性脑白质营养不良（MLD）的已知原因，MLD是一种常染色体隐性遗传性溶酶体贮积病。该研究描述了一名患有MLD和帕金森病家族史的患者。患者是两种罕见错义ARSA突变的复合杂合携带者，p.L300S（c. 899T> C，rs199476389）和p. C174Y（c. 521G> A，rs199476381）。在两名帕金森病家族成员和两名未受影响的成员中进行ARSA筛查，发现p.L300S突变与帕金森病分离，而不是p.C174Y突变。接下来，在92名家族性和92名散发性帕金森病患者中进行了ARSA的候选基因分析，并将结果与日本综合基因组变异数据库中的等位基因频率进行了比较。这种筛选鉴定出一种常见的错义变体，p.N352S（c. 1055 A> G，rs 2071421），这是更常见的健康日本人比家族性和散发性帕金森病病例（P= 0.026和P= 0.0349，分别）。作者得出结论，p.N352S变体可能对帕金森病的发展具有保护作用。他们还发现，ARSA缺乏会增加α-突触核蛋白的聚集和分泌，这表明ARSA突变与α-突触核蛋白病理学之间存在潜在联系。α-突触核蛋白病是一组异质性神经变性疾病，其特征在于特定神经元和神经胶质细胞的细胞质中不溶性α-突触核蛋白的纤维状聚集体。这些障碍包括帕金森病、路易体痴呆（LBD）、多系统萎缩（MSA）和REM-睡眠行为障碍（RBD），一种前驱α-突触核蛋白病（Goedert et al. 2017; Postuma等人，2019年）。遗传学的进展已经在几种α-突触核蛋白病的发病机制中涉及溶酶体功能障碍。例如，doi：10.1093/brain/awz 340 BRAIN 2019：142; 1-4中的变体|e70
Sir, We read with great interest the recently published article by Lee and colleagues reporting variants in ARSA and their association with Parkinson’s disease (Lee et al., 2019). Deficiency of arylsulfatase A is a known cause of metachromatic leukodystrophy (MLD), an autosomal recessive lysosomal storage disease. The study describes a patient with MLD and a family history of Parkinson’s disease. The patient was a compound heterozygous carrier of two rare missense ARSA mutations, p. L300S (c. 899T> C, rs199476389) and p. C174Y (c. 521G> A, rs199476381). Screening of ARSA in two family members with Parkinson’s disease and two unaffected members found that the p. L300S mutation segregated with Parkinson’s disease, but not the p. C174Y mutation. Next, a candidate gene analysis of ARSA was conducted in 92 familial and 92 sporadic Parkinson’s disease patients, and the results were compared to the allele frequencies within the Integrative Japanese Genome Variation Database. This screening identified a common missense variant, p. N352S (c. 1055A> G, rs2071421), that was more frequent in healthy Japanese individuals than in familial and sporadic Parkinson’s disease cases (P= 0.026 and P= 0.0349, respectively). The authors concluded that the p. N352S variant may be protective against the development of Parkinson’s disease. They also found that ARSA deficiency increases a-synuclein aggregation and secretion, suggesting a potential link between ARSA mutations and a-synuclein pathology. a-Synucleinopathies are a heterogeneous group of neurodegenerative disorders characterized by fibrillar aggregates of insoluble a-synuclein protein in the cytoplasm of specific neurons and glial cells. These disorders include Parkinson’s disease, Lewy body dementia (LBD), multiple system atrophy (MSA), and REM-sleep behaviour disorder (RBD), a prodromal a-synucleinopathy (Goedert et al., 2017; Postuma et al., 2019). Advances in genetics have implicated lysosomal dysfunction in the pathogenesis of several a-synucleinopathies. For example, variants within the doi: 10.1093/brain/awz340 BRAIN 2019: 142; 1–4| e70