CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications.
CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications.
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DOI：
10.3389/fnmol.2022.860662
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发表时间：
2022
影响因子：
4.8
通讯作者：
Wang, Jie
中科院分区：
文献类型：
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作者：
Li, Xue-Lian;Li, Zong-Jun;Liang, Xiao-Yu;Liu, De-Tian;Jiang, Mi;Gao, Liang-Di;Li, Huan;Tang, Xue-Qing;Shi, Yi-Wu;Li, Bing-Mei;He, Na;Li, Bin;Bian, Wen-Jun;Yi, Yong-Hong;Cheng, Chuan-Fang;Wang, Jie
关键词：
此前，据报道，电压门控钙通道亚基 α1 A (CACNA1A) 基因的突变与阵发性疾病相关，通常为阵发性共济失调 2 型。旨在确定 CACNA1A 与癫痫之间的关系以及分子亚区域对表型异质性的作用。对 318 例部分性癫痫病例和 150 例全身性癫痫病例进行了基于 Trio 的全外显子组测序。然后，我们回顾了之前报道的所有 CACNA1A 突变，并分析了基因型-表型相关性与分子亚区域影响。我们在十个不相关的癫痫病例中鉴定出 12 个 CACNA1A 突变，包括四个从头无效突变 (c.2963_2964insG/p.Gly989Argfs*78、c.3089 + 1G > A、c.4755 + 1G > T 和 c.6340-1G > A)、四个从头错义突变 (c.203G > T/p.Arg68Leu、c.3965G > A/p.Gly1322Glu、c.5032C > T/p.Arg1678Cys 和 c.5393C > T/p.Ser1798Leu)，以及两对复合杂合错义突变 (c.4891A > G/p.Ile1631Val& c.5978C > T/p.Pro1993Leu 和 c.3233C > T/p.Ser1078Leu&c.6061G > A/p.Glu2021Lys）。根据美国医学遗传学与基因组学学院（ACMG）的标准，将8个新生突变评估为致病性或可能致病性突变。该队列中发现的复合杂合 CACNA1A 突变的频率显着高于东亚和所有人群的对照（P = 7.30 × 10–4，P = 2.53 × 10–4）。尽管有 4 例患者频繁癫痫发作，但在抗癫痫治疗后，所有 10 例患者最终均无癫痫发作。进一步分析显示，2 型发作性共济失调 (EA2) 的无效突变频率比癫痫病更高。严重癫痫表型中的错义突变比轻度癫痫表型中的错义突变更频繁地位于孔区域（P = 1.67 × 10–4）；伴有智力障碍（ID）的癫痫患者的新生突变比例高于无智力障碍的癫痫患者（P = 1.92 × 10–3）。这项研究表明，CACNA1A 突变可能与单纯性癫痫相关，并且癫痫表型的范围可能从轻度癫痫（如失神性癫痫或部分性癫痫）到严重形式的发育性癫痫性脑病。临床表型变异可能与突变的分子亚区域相关。
Previously, mutations in the voltage-gated calcium channel subunit alpha1 A (CACNA1A) gene have been reported to be associated with paroxysmal disorders, typically as episodic ataxia type 2. To determine the relationship between CACNA1A and epilepsies and the role of molecular sub-regional on the phenotypic heterogeneity. Trio-based whole-exome sequencing was performed in 318 cases with partial epilepsy and 150 cases with generalized epilepsy. We then reviewed all previously reported CACNA1A mutations and analyzed the genotype-phenotype correlations with molecular sub-regional implications. We identified 12 CACNA1A mutations in ten unrelated cases of epilepsy, including four de novo null mutations (c.2963_2964insG/p.Gly989Argfs*78, c.3089 + 1G > A, c.4755 + 1G > T, and c.6340-1G > A), four de novo missense mutations (c.203G > T/p.Arg68Leu, c.3965G > A/p.Gly1322Glu, c.5032C > T/p.Arg1678Cys, and c.5393C > T/p.Ser1798Leu), and two pairs of compound heterozygous missense mutations (c.4891A > G/p.Ile1631Val& c.5978C > T/p.Pro1993Leu and c.3233C > T/p.Ser1078Leu&c.6061G > A/p.Glu2021Lys). The eight de novo mutations were evaluated as pathogenic or likely pathogenic mutations according to the criteria of American College of Medical Genetics and Genomics (ACMG). The frequencies of the compound heterozygous CACNA1A mutations identified in this cohort were significantly higher than that in the controls of East Asian and all populations (P = 7.30 × 10–4, P = 2.53 × 10–4). All of the ten cases were ultimately seizure-free after antiepileptic treatment, although frequent epileptic seizures were observed in four cases. Further analysis revealed that episodic ataxia type 2 (EA2) had a tendency of higher frequency of null mutations than epilepsies. The missense mutations in severe epileptic phenotypes were more frequently located in the pore region than those in milder epileptic phenotypes (P = 1.67 × 10–4); de novo mutations in the epilepsy with intellectual disability (ID) had a higher percentage than those in the epilepsy without ID (P = 1.92 × 10–3). This study suggested that CACNA1A mutations were potentially associated with pure epilepsy and the spectrum of epileptic phenotypes potentially ranged from the mild form of epilepsies such as absence epilepsy or partial epilepsy, to the severe form of developmental epileptic encephalopathy. The clinical phenotypes variability is potentially associated with the molecular sub-regional of the mutations.
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