Dataset Information

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.

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.

SUBMITTER: Furey CG

PROVIDER: S-EPMC7839075 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.

Furey Charuta Gavankar CG Choi Jungmin J Jin Sheng Chih SC Zeng Xue X Timberlake Andrew T AT Nelson-Williams Carol C Mansuri M Shahid MS Lu Qiongshi Q Duran Daniel D Panchagnula Shreyas S Allocco August A Karimy Jason K JK Khanna Arjun A Gaillard Jonathan R JR DeSpenza Tyrone T Antwi Prince P Loring Erin E Butler William E WE Smith Edward R ER Warf Benjamin C BC Strahle Jennifer M JM Limbrick David D DD Storm Phillip B PB Heuer Gregory G Jackson Eric M EM Iskandar Bermans J BJ Johnston James M JM Tikhonova Irina I Castaldi Christopher C López-Giráldez Francesc F Bjornson Robert D RD Knight James R JR Bilguvar Kaya K Mane Shrikant S Alper Seth L SL Haider Shozeb S Guclu Bulent B Bayri Yasar Y Sahin Yener Y Apuzzo Michael L J MLJ Duncan Charles C CC DiLuna Michael L ML Günel Murat M Lifton Richard P RP Kahle Kristopher T KT

Neuron 20180705 2

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<sup>-7</sup>), SMARCC1 (p = 8.15 × 10<sup>-10</sup>), an ...[more]

PMID: 29983323

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Project description:BackgroundCongenital myopathy (CM) is a group of clinically and genetically heterogeneous muscle disorders, characterized by muscle weakness and hypotonia from birth. Currently, no definite treatment exists for CM. A de novo mutation in Tropomyosin 3-TPM3(E151G) was identified from a boy diagnosed with CM, previously TPM3(E151A) was reported to cause CM. However, the role of TPM3(E151G) in CM is unknown.MethodsHistopathological, swimming behavior, and muscle endurance were monitored in TPM3 wild-type and mutant transgenic fish, modelling CM. Gene expression profiling of muscle of the transgenic fish were studied through RNAseq, and mitochondria respiration was investigated.ResultsWhile TPM3(WT) and TPM3(E151A) fish show normal appearance, amazingly a few TPM3(E151G) fish display either no tail, a crooked body in both F0 and F1 adults. Using histochemical staining for the muscle biopsy, we found TPM3(E151G) displays congenital fiber type disproportion and TPM3(E151A) resembles nemaline myopathy. TPM3(E151G) transgenic fish dramatically swimming slower than those in TPM3(WT) and TPM3(E151A) fish measured by DanioVision and T-maze, and exhibit weaker muscle endurance by swimming tunnel instrument. Interestingly, L-carnitine treatment on TPM3(E151G) transgenic larvae significantly improves the muscle endurance by restoring the basal respiration and ATP levels in mitochondria. With RNAseq transcriptomic analysis of the expression profiling from the muscle specimens, it surprisingly discloses large downregulation of genes involved in pathways of sodium, potassium, and calcium channels, which can be rescued by L-carnitine treatment, fatty acid metabolism was differentially dysregulated in TPM3(E151G) fish and rescued by L-carnitine treatment.ConclusionsThese results demonstrate that TPM3(E151G) and TPM3(E151A) exhibit different pathogenicity, also have distinct gene regulatory profiles but the ion channels were downregulated in both mutants, and provides a potential mechanism of action of TPM3 pathophysiology. Our results shed a new light in the future development of potential treatment for TPM3-related CM.

Dataset Information

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.

Publications

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.

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