title: TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.
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.
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Ba
authors.affiliation: Department of Neuroscience, UCONN Health Center, Farmington, CT 06030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Human Genetics.
authors.forename: Margot R F
authors.initials: MR
authors.lastname: Reijnders
authors.affiliation: Department of Human Genetics.
authors.forename: Janneke H M
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.affiliation: Department of Human Genetics.
authors.forename: Ilse
authors.initials: I
authors.lastname: Feenstra
authors.affiliation: Department of Human Genetics.
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.affiliation: 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.
authors.forename: Daniëlle G M
authors.initials: DG
authors.lastname: Bosch
authors.affiliation: Department of Human Genetics.
authors.forename: Nicole
authors.initials: N
authors.lastname: De Leeuw
authors.affiliation: Department of Human Genetics.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Human Genetics.
authors.forename: Petra F
authors.initials: PF
authors.lastname: De Vries
authors.affiliation: 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.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Human Genetics.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA, Howard Hughes Medical Institute, Seattle, WA 98195, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: Department of Human Genetics.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: 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.
authors.forename: Nael
authors.initials: N
authors.lastname: Nadif Kasri
authors.affiliation: 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.
authors.forename: Bert B A
authors.initials: BB
authors.lastname: De Vries
mesh_terms: D000328:Adult; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D005260:Female; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D011595:Psychomotor Agitation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D017346:Protein Serine-Threonine Kinases; C099628:TRIO protein, human