Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders
Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders
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DOI：
10.1093/brain/awaa346
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发表时间：
2020-12-01
期刊：
影响因子：
14.5
通讯作者：
Depienne, Christel
中科院分区：
文献类型：
--
作者：
Mochel, Fanny;Rastetter, Agnes;Depienne, Christel
KCNN 2编码小电导钙激活钾通道2（SK2）。具有自发KCNN 2突变的啮齿动物模型显示异常步态和运动活动、震颤和记忆缺陷，但与KCNN 2变体相关的人类疾病在很大程度上是未知的。利用外显子组测序，我们发现了一个从头KCNN 2移码缺失的患者学习障碍，小脑共济失调和脑MRI上的白色物质异常。这一发现促使我们从另外9名患有从头KCNN 2变体（一个无义，一个剪接位点，六个错义变体和一个框内缺失）的患者和一个从受影响母亲遗传的错义变体家族中收集数据。我们使用膜片钳技术研究了六种选定的变体对SK2通道功能的功能影响。除一种变体（重新分类为不确定显著性）外，所有检测的变体均导致SK 2通道功能丧失。KCNN 2变异患者有运动和语言发育迟缓，智力残疾通常与早发性运动障碍相关，包括小脑共济失调和/或锥体外系症状。总而言之，我们的研究结果提供的证据表明，杂合变异，可能导致KCNN 2基因的单倍不足，导致新的常染色体显性遗传神经发育运动障碍，反映了先前在啮齿动物中描述的表型。
KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.