Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen and German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Mov Disord. 2021 Jul;36(7):1624-1633. doi: 10.1002/mds.28534. Epub 2021 Feb 22.
The SNCA gene encoding α-synuclein (αSyn) is the first gene identified to cause autosomal-dominant Parkinson's disease (PD).
We report the identification of a novel heterozygous A30G mutation of the SNCA gene in familial PD and describe clinical features of affected patients, genetic findings, and functional consequences.
Whole exome sequencing was performed in the discovery family proband. Restriction digestion with Bbvl was used to screen SNCA A30G in two validation cohorts. The Greek cohort included 177 familial PD probands, 109 sporadic PD cases, and 377 neurologically healthy controls. The German cohort included 136 familial PD probands, 380 sporadic PD cases, and 116 neurologically healthy controls. We also conducted haplotype analysis using 13 common single nucleotide variants around A30G to determine the possibility of a founder effect for A30G. We then used biophysical methods to characterize A30G αSyn.
We identified a novel SNCA A30G (GRCh37, Chr4:90756730, c.89 C>G) mutation that co-segregated with the disease in five affected individuals of three Greek families and was absent from controls. A founder effect was strongly suggested by haplotype analysis. The A30G mutation had a local effect on the intrinsically disordered structure of αSyn, slightly perturbed membrane binding, and promoted fibril formation.
Based on the identification of A30G co-segregating with the disease in three families, the absence of the mutation in controls and population databases, and the observed functional effects, we propose SNCA A30G as a novel causative mutation for familial PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
编码α-突触核蛋白（αSyn）的 SNCA 基因是首个被确定导致常染色体显性遗传帕金森病（PD）的基因。
我们报道了在家族性 PD 中发现的 SNCA 基因的新型杂合 A30G 突变，并描述了受影响患者的临床特征、遗传发现和功能后果。
对先证者进行全外显子组测序。在两个验证队列中使用 Bbvl 进行 SNCA A30G 的限制性消化。希腊队列包括 177 名家族性 PD 先证者、109 名散发性 PD 病例和 377 名神经健康对照者。德国队列包括 136 名家族性 PD 先证者、380 名散发性 PD 病例和 116 名神经健康对照者。我们还使用 A30G 周围的 13 个常见单核苷酸变异进行单倍型分析，以确定 A30G 有无可能存在一个共同的起源。然后，我们使用生物物理方法来表征 A30GαSyn。
我们发现了一种新型的 SNCA A30G（GRCh37，Chr4：90756730，c.89 C>G）突变，该突变与三个希腊家族的五名受影响个体中的疾病共分离，且在对照组中不存在。单倍型分析强烈提示存在一个共同的起源。A30G 突变对 αSyn 的无规卷曲结构具有局部影响，略微扰乱了膜结合，并促进了纤维形成。
基于在三个家族中发现 A30G 与疾病共分离、在对照组和人群数据库中未发现该突变，以及观察到的功能影响，我们提出 SNCA A30G 是家族性 PD 的一个新的致病突变。
