De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.
De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.
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DOI：
10.1016/j.neuron.2018.06.019
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发表时间：
2018-07-25
期刊：
影响因子：
16.2
通讯作者：
Kahle KT
中科院分区：
文献类型：
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作者：
Furey CG;Choi J;Jin SC;Zeng X;Timberlake AT;Nelson-Williams C;Mansuri MS;Lu Q;Duran D;Panchagnula S;Allocco A;Karimy JK;Khanna A;Gaillard JR;DeSpenza T;Antwi P;Loring E;Butler WE;Smith ER;Warf BC;Strahle JM;Limbrick DD;Storm PB;Heuer G;Jackson EM;Iskandar BJ;Johnston JM;Tikhonova I;Castaldi C;López-Giráldez F;Bjornson RD;Knight JR;Bilguvar K;Mane S;Alper SL;Haider S;Guclu B;Bayri Y;Sahin Y;Apuzzo MLJ;Duncan CC;DiLuna ML;Günel M;Lifton RP;Kahle KT
先天性脑积水(CH)以脑室明显增大为特征，被认为是由于脑脊液(CSF)内环境平衡失败而引起的，并接受终身外科脑脊液分流术治疗，但发病率很高。CH的发病机制尚不清楚。对12 5个CH Trio和5 2个先证者的外显子组测序发现，有3个基因具有罕见的新生或传递突变的显著负担：TRIM71(p=2.15×10−7)、SMARCC1(p=8.15×10−10)和ptch1(p=1.0 6×10−6)。此外，在SHH基因座还发现了两个编码PTCH1配体的从头重复序列(p=1.2×10−4)。这些先证者加起来约占研究病例的10%。值得注意的是，所有四个基因都是神经管发育所必需的，并调节脑室区神经干细胞的命运。这些结果表明，神经发生受损(而不是活跃的脑脊液积聚)与部分CH患者的发病有关，具有潜在的诊断、预后和治疗分支。先天性脑积水(CH)是儿童发病率和死亡率的主要原因，每1000名活产儿中就有1名受到影响，占所有儿科住院费用的3%。利用迄今为止最大的CH外显子组测序研究的数据，Furey等人。鉴定出四个以前未涉及到的CH.值得注意的是，这四个基因都控制着脑室区神经干细胞的命运，加在一起可以解释大约10%的脑出血病例。这些发现表明，在相当数量的CH患者的发病机制中，神经发生受损，具有潜在的诊断、预后和治疗分支。
Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10−7), SMARCC1 (p = 8.15 × 10−10), and PTCH1 (p = 1.06 × 10−6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10−4). Together, these probands account for ~10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications. Congenital hydrocephalus (CH) is a major cause of childhood morbidity and mortality, affecting 1 in 1,000 live births and representing up to 3% of all pediatric hospital charges. Using data from the largest CH exome sequencing study to date, Furey et al. identify four genes (TRIM71, SMARCC1, PTCH1, and SHH) not previously implicated in CH. Remarkably, all four genes regulate ventricular zone neural stem cell fate and, together, explain ~10% of CH cases. These findings implicate impaired neurogenesis in pathogenesis of a significant number of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
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