De novo CACNA1G variants in developmental delay and early-onset epileptic encephalopathies
De novo CACNA1G variants in developmental delay and early-onset epileptic encephalopathies
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DOI：
10.1016/j.jns.2020.117047
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发表时间：
2020-09-15
影响因子：
4.4
通讯作者：
Tanaka, Fumiaki
中科院分区：
文献类型：
--
作者：
Kunii, Misako;Doi, Hiroshi;Tanaka, Fumiaki
简介：方法：对348例日本神经发育障碍患者及其父母的基因组DNA进行全外显子组测序，提取CACNA 1G的新生变异体。每个突变通道的电生理特性进行了研究，通过电压钳和电流钳分析HEK 293 T细胞过表达这些channel.Results：两名患者被诊断为Rett综合征和西方综合征被发现有已知的病理CACNA 1G突变小脑共济失调队列报告：c.2881G > A，p.Ala961Thr和c.4591A > G，p.Met1531Val，分别。1例Lennox-Gastaut综合征患者发现了一种以前未报道的杂合变异：c.3817A > T，p.Ile1273Phe。两名已知突变的患者的临床症状包括严重的发育迟缓，没有获得独立行走的能力。具有潜在新突变的患者在MRI上显示发育迟缓、难治性癫痫发作和轻度脑萎缩，但症状的严重程度比前两例轻。HEK 293 T细胞的电生理研究表明，p.Ala961Thr和p.Met1531Val SNV显著改变了T型Ca 2+电流，这可能增强了低频下的膜电位振荡。与此相反，p.Ile1273Phe没有表现出显着的影响，在我们的电生理评价，其发病机制仍然undetermined.Conclusion：从头变异CACNA 1G解释一些神经发育障碍。我们的研究进一步提供了信息，以了解与CACNA 1G突变患者的基因型-表型相关性。
Introduction: Variants of CACNA1G, which encodes CaV3.1, have been reported to be associated with various neurological disorders.Methods: Whole-exome sequencing of genomic DNA from 348 Japanese patients with neurodevelopmental disorders and their parents was conducted, and de novo variants of CACNA1G were extracted. The electrophysiological properties of each mutant channel were investigated by voltage-clamp and current-clamp analyses of HEK293T cells overexpressing these channels.Results: Two patients diagnosed with Rett syndrome and West syndrome were found to have known pathological CACNA1G mutations reported in cerebellar ataxia cohorts: c.2881G > A, p.Ala961Thr and c.4591A > G, p.Met1531Val, respectively. One patient with Lennox-Gastaut syndrome was revealed to harbor a previously unreported heterozygous variant: c.3817A > T, p.Ile1273Phe. Clinical symptoms of the two patients with known mutations included severe developmental delay without acquisition of the ability to walk independently. The patient with a potentially novel mutation showed developmental delay, intractable seizures, and mild cerebral atrophy on MRI, but the severity of symptoms was milder than in the former two cases. Electrophysiological study using HEK293T cells demonstrated significant changes of T-type Ca2+ currents by p.Ala961Thr and p.Met1531Val SNVs, which were likely to enhance oscillation of membrane potential at low frequencies. In contrast, p.Ile1273Phe showed no significant effects in our electrophysiological evaluations, with its pathogenesis remaining undetermined.Conclusion: De novo variants of CACNA1G explain some neurodevelopmental disorders. Our study further provides information to understand the genotype-phenotype correlations of patients with CACNA1G mutations.