原发性震颤(ET)是较为常见的运动障碍之一。目前的诊断仅基于临床发现。ET似乎以常染色体显性遗传模式遗传。已通过连锁分析研究了特定染色体上的几个基因座,但是许多患者的特发性震颤的原因仍然未知。遗传研究描述了几种基因与家族性ET的关联。然而,它们只在不同的家庭中被发现,这表明有些可能是私人致病变种。
表征具有ET的意大利家族的表型并鉴定相关的遗传变异。
进行临床和基因检查。使用Illumina平台用全外显子组测序(WES)进行遗传测试。使用双向毛细管Sanger测序来研究该家族的所有受影响成员中变体的存在。致病性的计算机预测用于研究基因变体对蛋白质结构的影响。
先证者是一个15岁的男孩。该患者是一对非近亲夫妇的两个孩子中的第一个。家族史在母系震颤中是显着的。他的母亲患有双侧上肢运动性震颤(自20岁起),焦虑,和抑郁症。其他亲属提及双侧上肢震颤。在索引情况下,WES分析假设遗传的主导模式,在钾钙激活通道亚家族N成员2(KCNN2)中鉴定出一个新的杂合错义变体(NM_021614.3:c.1145G>A,p.Gly382Asp)。在血统调查中,所有基因变异的携带者都有ET并表现出可变的表达能力,在过去的十年中,有症状的老年人亲属表现出认知障碍和幻觉,除了年轻时的震颤。氨基酸残基#382位于跨膜区,并且计算机模拟分析表明该变体的致病作用。突变蛋白质结构的建模表明,该变体在蛋白质结构中引起冲突。因此,该变异可能引起构象变化,从而改变蛋白质在离子通道调节中的能力。结论:鉴定出的KCNN2基因变异可能与ET有关。该变体可以修饰由细胞内钙激活的电压依赖性钾通道。
Essential tremor (ET) is one of the more common movement disorders. Current diagnosis is solely based on clinical findings. ET appears to be inherited in an autosomal dominant pattern. Several loci on specific chromosomes have been studied by linkage analysis, but the causes of essential tremor are still unknown in many patients. Genetic studies described the association of several genes with familial ET. However, they were found only in distinct families, suggesting that some can be private pathogenic variants.
to characterize the phenotype of an Italian family with ET and identify the genetic variant associated.
Clinical and genetic examinations were performed. Genetic testing was done with whole-exome sequencing (WES) using the Illumina platform. Bidirectional capillary Sanger sequencing was used to investigate the presence of variant in all affected members of the family. In silico prediction of pathogenicity was used to study the effect of gene variants on protein structure.
The proband was a 15-year-old boy. The patient was the first of two children of a non-consanguineous couple. Family history was remarkable for tremor in the mother line. His mother suffered from bilateral upper extremity kinetic tremors (since she was 20 years old), anxiety, and depression. Other relatives referred bilateral upper extremity tremors. In the index case, WES analysis performed supposing a dominant mode of inheritance, identified a novel heterozygous missense variant in potassium calcium-activated channel subfamily N member 2 (
KCNN2) (NM_021614.3: c.1145G>A, p.Gly382Asp). In the pedigree investigation, all carriers of the gene variant had ET and showed variable expressivity, the elder symptomatic relative showing cognitive impairment and hallucinations in the last decade, in addition to tremor since a young age. The amino acid residue #382 is located in a transmembrane region and in silico analysis suggested a causative role for the variant. Modelling of the mutant protein structure showed that the variant causes a clash in the protein structure. Therefore, the variant could cause a conformational change that alters the ability of the protein in the modulation of ion channels Conclusions: The
KCNN2 gene variant identified could be associated with ET. The variant could modify a voltage-independent potassium channel activated by intracellular calcium.