Identification of candidate genes for familial early-onset essential tremor
Identification of candidate genes for familial early-onset essential tremor
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DOI：
10.1038/ejhg.2015.228
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发表时间：
2016-07-01
影响因子：
5.2
通讯作者：
Clark, Lorraine N.
中科院分区：
文献类型：
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作者：
Liu, Xinmin;Hernandez, Nora;Clark, Lorraine N.
原发性震颤(ET)是人类最常见的震颤原因之一。尽管其遗传性和患病率很高，但几乎没有发现ET的易感基因。为了确定ET基因，对37个具有常染色体显性遗传模式的早发性ET家系进行了全外显子组测序。我们在五个ET家系中确定了用于后续功能研究的候选基因。在两个独立的家系中，我们发现了预测会影响一氧化氮合成酶3基因(NOS3)功能的变异，这些变异与疾病存在协同分离。NOS3在中枢神经系统(包括小脑)、神经元和内皮细胞中高表达，是将L精氨酸转化为神经递质NO的三种酶之一。在一个家系中，在NOS3中，在3例ET患者中发现了杂合突变c.46G>；A(p.(Gly16Ser))，在1个未发病的家庭成员中缺失；在另一个家系中，在3例ET患者(双胞胎及其母亲)中发现了杂合突变c.164C>；T(p.(Pro55Leu))。这两个变异体都会导致高度保守的氨基酸残基的氨基酸替换，这些氨基酸残基在电子分析中被预测是有害和有害的。在三个独立的家系中，预测会影响功能的变异也在其他基因中被发现，包括KCNS2(KV9.2)、HAPLN4(BRAL2)和USP46。这些基因在小脑和浦肯野细胞中高表达，并影响γ-氨基丁酸(GABA)能系统的功能。这与最近的证据一致，即ET的病理生理过程涉及小脑功能障碍和可能的小脑变性，浦肯野细胞减少，GABA能神经递质减少。
Essential tremor (ET) is one of the most common causes of tremor in humans. Despite its high heritability and prevalence, few susceptibility genes for ET have been identified. To identify ET genes, whole-exome sequencing was performed in 37 early-onset ET families with an autosomal-dominant inheritance pattern. We identified candidate genes for follow-up functional studies in five ET families. In two independent families, we identified variants predicted to affect function in the nitric oxide (NO) synthase 3 gene (NOS3) that cosegregated with disease. NOS3 is highly expressed in the central nervous system (including cerebellum), neurons and endothelial cells, and is one of three enzymes that converts L-arginine to the neurotransmitter NO. In one family, a heterozygous variant, c.46G>A (p.(Gly16Ser)), in NOS3, was identified in three affected ET cases and was absent in an unaffected family member; and in a second family, a heterozygous variant, c.164C>T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved amino-acid residues that are predicted to be deleterious and damaging by in silico analysis. In three independent families, variants predicted to affect function were also identified in other genes, including KCNS2 (KV9.2), HAPLN4 (BRAL2) and USP46. These genes are highly expressed in the cerebellum and Purkinje cells, and influence function of the gamma-amino butyric acid (GABA)-ergic system. This is in concordance with recent evidence that the pathophysiological process in ET involves cerebellar dysfunction and possibly cerebellar degeneration with a reduction in Purkinje cells, and a decrease in GABA-ergic tone.