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Hum Mol Genet. 2016 Mar 1;25(5):892-902. doi: 10.1093/hmg/ddv618. Epub 2015 Dec 31.

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

Author information

1
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.
2
Department of Neuroscience, UCONN Health Center, Farmington, CT 06030, USA.
3
Department of Human Genetics.
4
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.
5
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.
6
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
7
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA, Howard Hughes Medical Institute, Seattle, WA 98195, USA.
8
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.
9
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.

Abstract

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.

PMID:
26721934
PMCID:
PMC4754042
[Available on 2017-03-01]
DOI:
10.1093/hmg/ddv618
[Indexed for MEDLINE]
Free PMC Article

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