biostudies-literatureDuy PQRudi Schulte Research Institute Hydrocephalus Association Innovator AwardU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesNICHD NIH HHSHydrocephalus Association Innovator AwardNIAID NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesNHLBI NIH HHSNIMH NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on Drug AbuseU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood InstituteCareer Award at the Scientific Interfaces from Burroughs Welcome FundU.S. Department of Health & Human Services | NIH | National Institute of Mental HealthU.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeDeutsche ForschungsgemeinschaftNINDS NIH HHSNIGMS NIH HHS458-473https://www.ebi.ac.uk/biostudies/studies/S-EPMC9664907biostudies-literatureUnknown25(4)Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets,Nature neuroscienceImpaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.PMC9664907R01 MH113257DA023999DP2 AI138259R01 NS1229041DP2AI138259-01T32 GM136651R00 HL1430365R21NS116484-02F30HD106694WU 563/3-1RO1NS111029T32GM136651R21 NS116484R00HL143036-021R21NS121642-01R21 NS1216421R01NS122904-01EXC2151 – 390873048F30 HD106694NIH MH113257Dahl PJDong WJux BDuy PQWeise SCLi XJSchultze JLLiang DHandler KSingh AKCarter BSKiziltug EHao LTNelson-Williams CWalsh CAMoreno-De-Luca AAllington GGoto JReeves BCKim SKRakic PRobert SMPedram MZSousa AMMPaeschke KDuque AEstrada-Veras JILi MHa YDoetzlhofer AConstable RTKahle KTYang YUlas TCuevas ESelvaganesan KButler WELin HTimberlake ATMa SBecker MDeniz ETakeo YKoundal SMalvankar NSSestan NBenveniste HJuranek SAKundishora AJJuusola JFurey CGYu XJin SCDe Domenico EDunbar ASmith HAlper SLSpajic AWulczyn FGKolanus WLake EMRMarini CMarlier ATorres-Fernandez LALifton RPLiu FDeSpenza TfalseImpaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets,2022-01-01T00:00:00Z2022 Apr2025-04-25T23:21:18.947Z2025-04-06T09:22:08.521ZS-EPMC96649073537999510.1038/s41593-022-01043-3