Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders
Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders
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DOI：
10.1016/j.ajhg.2021.06.003
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发表时间：
2021-08-05
影响因子：
9.8
通讯作者：
Agrawal, Pankaj B.
中科院分区：
文献类型：
--
作者：
Duncan, Anna R.;Polovitskaya, Maya M.;Agrawal, Pankaj B.
全面发育迟缓（GDD）和智力残疾（ID）的遗传原因是多种多样的，包括许多离子通道和转运蛋白的变异。Cl-通道和Cl-/H+交换剂的CLC家族的所有五个内体/溶酶体成员中的功能丧失变体导致小鼠、人类或两者中的病理学。我们在11名患有不同严重程度的GDD/ID和神经发育障碍的个体中确定了CLCN 3（编码CIC-3的基因）的9种变体。除了两个同胞中的纯合移码变异外，我们还发现了8种不同的杂合从头错义变异。所有人都有GDD/ID，情绪或行为障碍和畸形特征; 9/11人有脑结构异常; 6/11人有癫痫发作。预测纯合变体引起ClC-3功能丧失，导致与Clcn 3（-/-）小鼠中观察到的表型相似的严重神经系统疾病。他们的MRI显示可能的神经退行性变，胼胝体变薄，白色物质体积减少。具有杂合子变异的个体具有一系列神经发育异常，包括胼胝体发育不全、脑桥发育不全和脑回折叠增加。为了表征交换器功能的改变，在非洲爪蟾卵母细胞和哺乳动物细胞中进行了电生理分析。两个变种，p.Ile607Thr和p.Thr570Ile，增加了电流在负的细胞质电压和管腔酸性pH值的抑制损失。相反，其他两个变种没有表现出显着差异的电流特性。总的来说，我们的工作确立了CLCN 3在人类神经发育中的作用，并表明ClC-3的纯合缺失和杂合变体均可导致GDD/ID和神经解剖学异常。
The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3(-/-) mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.