Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures
Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures
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DOI：
10.1016/j.ajhg.2016.03.011
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发表时间：
2016-05-05
影响因子：
9.8
通讯作者：
Goldstein, David B.
中科院分区：
文献类型：
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作者：
Petrovski, Slave;Kury, Sebastien;Goldstein, David B.
对 13 名发育迟缓且通常伴有肌张力异常和癫痫发作的个体进行全外显子组测序，发现在 GNB1（编码鸟嘌呤核苷酸结合蛋白亚基 beta-1（G beta）的基因）的一个亚区域内富集了从头错义突变。这 13 个人是在 5,855 名因各种未确诊遗传性疾病而招募的人中被识别出来的。在 5,855 名个体中偶然观察到 13 个或更多从头突变的概率非常低 (p = 7.1 x 10(-21))，这表明 GNB1 是一种全基因组显着的疾病相关基因。这 13 个突变中的大多数影响已知的 G β 结合位点，这表明可能的疾病机制是通过破坏 G α-G β γ 相互作用所需的蛋白质界面（导致组成性活跃的 G β γ ）或通过破坏与 G β γ 和某些下游效应器之间相互作用相关的残基（导致与效应器的相互作用减少）。引人注目的是，这里招募的 13 名神经发育障碍患者中，有 8 人具有种系从头 GNB1 突变，该突变与一组 5 个复发性体细胞肿瘤突变重叠，最近的功能研究表明，由于某些受影响残基的 G 蛋白下游信号级联的组成性激活，具有功能获得效应。
Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, G beta. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 x 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known G beta binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for G alpha-G beta gamma interaction (resulting in a constitutively active G beta gamma) or through the disruption of residues relevant for interaction between G beta gamma and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.