Furey, CG;
Choi, J;
Jin, SC;
Zeng, X;
Timberlake, AT;
Nelson-Williams, C;
Mansuri, MS;
... Kahle, KT; + view all
(2018)
De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.
Neuron
, 99
(2)
pp. 302-314.
10.1016/j.neuron.2018.06.019.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.neuron.2018.06.019 |
| Publisher version: | https://doi.org/10.1016/j.neuron.2018.06.019 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | congenital hydrocephalus, aqueductal stenosis, whole-exome sequencing, de novo variants, gene discovery, TRIM71m SMARCC1m PTCH1m SHH, neural stem cell |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10052459 |
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