دورية أكاديمية
أعرض في EDS

TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.

التفاصيل البيبلوغرافية
العنوان: TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.
المؤلفون: Ba W; Department of Human Genetics, Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands., Yan Y; Department of Neuroscience, UCONN Health Center, Farmington, CT 06030, USA., Reijnders MR; Department of Human Genetics., Schuurs-Hoeijmakers JH; Department of Human Genetics., Feenstra I; Department of Human Genetics., Bongers EM; Department of Human Genetics., Bosch DG; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands, Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands and., De Leeuw N; Department of Human Genetics., Pfundt R; Department of Human Genetics., Gilissen C; Department of Human Genetics., De Vries PF; Department of Human Genetics., Veltman JA; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands, Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands., Hoischen A; Department of Human Genetics., Mefford HC; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA., Eichler EE; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA, Howard Hughes Medical Institute, Seattle, WA 98195, USA., Vissers LE; Department of Human Genetics., Nadif Kasri N; Department of Human Genetics, Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands, bert.devries@radboudumc.nl n.nadif@donders.ru.nl., De Vries BB; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands, bert.devries@radboudumc.nl n.nadif@donders.ru.nl.
المصدر: Human molecular genetics [Hum Mol Genet] 2016 Mar 01; Vol. 25 (5), pp. 892-902. Date of Electronic Publication: 2015 Dec 31.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-
مواضيع طبية MeSH: Mutation*, Autistic Disorder/*genetics , Guanine Nucleotide Exchange Factors/*genetics , Intellectual Disability/*genetics , Neurons/*metabolism , Protein Serine-Threonine Kinases/*genetics , Psychomotor Agitation/*genetics , Synapses/*metabolism, Adult ; Animals ; Autistic Disorder/metabolism ; Autistic Disorder/pathology ; Child ; Female ; Gene Expression ; Guanine Nucleotide Exchange Factors/deficiency ; Hippocampus/metabolism ; Hippocampus/pathology ; Humans ; Intellectual Disability/metabolism ; Intellectual Disability/pathology ; Male ; Neurogenesis ; Neurons/pathology ; Primary Cell Culture ; Protein Serine-Threonine Kinases/deficiency ; Psychomotor Agitation/metabolism ; Psychomotor Agitation/pathology ; Rats ; Sequence Analysis, DNA ; Severity of Illness Index ; Synapses/pathology
مستخلص: Recently, we marked TRIO for the first time as a candidate gene for intellectual disability (ID). Across diverse vertebrate species, TRIO is a well-conserved Rho GTPase regulator that is highly expressed in the developing brain. However, little is known about the specific events regulated by TRIO during brain development and its clinical impact in humans when mutated. Routine clinical diagnostic testing identified an intragenic de novo deletion of TRIO in a boy with ID. Targeted sequencing of this gene in over 2300 individuals with ID, identified three additional truncating mutations. All index cases had mild to borderline ID combined with behavioral problems consisting of autistic, hyperactive and/or aggressive behavior. Studies in dissociated rat hippocampal neurons demonstrated the enhancement of dendritic formation by suppressing endogenous TRIO, and similarly decreasing endogenous TRIO in organotypic hippocampal brain slices significantly increased synaptic strength by increasing functional synapses. Together, our findings provide new mechanistic insight into how genetic deficits in TRIO can lead to early neuronal network formation by directly affecting both neurite outgrowth and synapse development.
(© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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معلومات مُعتمدة: R01 MH101221 United States MH NIMH NIH HHS; R01 NS069605 United States NS NINDS NIH HHS; U54 HD083091 United States HD NICHD NIH HHS; United States Howard Hughes Medical Institute
المشرفين على المادة: 0 (Guanine Nucleotide Exchange Factors)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.11.1 (TRIO protein, human)
تواريخ الأحداث: Date Created: 20160102 Date Completed: 20161213 Latest Revision: 20211203
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC4754042
DOI: 10.1093/hmg/ddv618
PMID: 26721934
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2083
DOI:10.1093/hmg/ddv618