Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability
Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability
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DOI：
10.1016/j.ajhg.2011.02.001
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发表时间：
2011-03-11
影响因子：
9.8
通讯作者：
Michaud, Jacques L.
中科院分区：
文献类型：
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作者：
Hamdan, Fadi F.;Gauthier, Julie;Michaud, Jacques L.
人们对非综合征性智力障碍（NSID）的遗传学知之甚少。我们假设突触基因的新生突变 (DNM) 解释了散发性 NSID 病例的重要部分。为了研究这种可能性，我们对 95 例散发性 NSID 病例中的 197 个编码谷氨酸受体及其已知相互作用蛋白的一大部分基因进行了测序。我们发现了 11 个 DNM，包括 8 个不同基因中的 10 个潜在有害突变（3 个无义突变、2 个剪接突变、1 个移码突变、4 个错义突变）和 1 个中性突变（沉默突变）。对每个功能和中性位点的点替换 DNM 率的计算表明，与中性位点相比，功能性 DNM 明显过量。在 6 名患者中发现了 SYNGAP1、STXBP1 和 SHANK3 的从头截短和/或剪接突变，并且可能具有致病性。在 KIF1A、GRIN1、CACNG2 和 EPB41L1 中发现了从头错义突变。功能研究表明，所有这些错义突变都会影响细胞培养系统中的蛋白质功能，表明它们可能具有致病性。对另外 50 个散发性 NSID 病例中的这四个基因进行测序，发现了 GRIN1 中的第二个 DNM (c.1679_1681dup/p.Ser560dup)。这种突变也会影响蛋白质功能，与结构预测一致。在 285 名健康对照者的这些基因中，没有发现任何突变或任何其他 DNM。这项研究强调了谷氨酸受体复合物在 NSID 中的重要性，并进一步支持 DNM 在这种疾病中的作用。
Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.