<i>TRIO</i>loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function

Ba, Wang; Yan, Yan; Reijnders, Margot R.F.; Schuurs-Hoeijmakers, Janneke; Feenstra, Ilse; Bongers, Ernie M.H.F.; Bosch, Daniëlle G.M.; Leeuw, Nicole de; Pfundt, Rolph; Gilissen, Christian; Vries, Petra F. de; Veltman, Joris A.; Hoischen, Alexander; Mefford, Heather C; Eichler, Evan E.; Vissers, Lisenka E.L.M.; Kasri, Nael Nadif; Vries, Bert B.A. de

doi:10.1093/hmg/ddv618

Cited by 89 publications

(105 citation statements)

References 54 publications

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“…This presentation aligns with the phenotype recently presented by Ba et al ,3 who screened 2300 ID cases and identified four truncating mutations in TRIO. Similarly, they described skeletal anomalies, short stature, feeding difficulties and facial asymmetry.…”

Section: Discussionsupporting

confidence: 89%

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Mutations specific to the Rac-GEF domain ofTRIOcause intellectual disability and microcephaly

Pengelly¹,

Greville‐Heygate²,

Schmidt³

et al. 2016

J Med Genet

105

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BackgroundNeurodevelopmental disorders have challenged clinical genetics for decades, with over 700 genes implicated and many whose function remains unknown. The application of whole-exome sequencing is proving pivotal in closing the genotype/phenotype gap through the discovery of new genes and variants that help to unravel the pathogenic mechanisms driving neuropathogenesis. One such discovery includes TRIO, a gene recently implicated in neurodevelopmental delay. Trio is a Dbl family guanine nucleotide exchange factor (GEF) and a major regulator of neuronal development, controlling actin cytoskeleton dynamics by activating the GTPase Rac1.MethodsWhole-exome sequencing was undertaken on a family presenting with global developmental delay, microcephaly and mild dysmorphism. Father/daughter exome analysis was performed, followed by confirmatory Sanger sequencing and segregation analysis on four individuals. Three further patients were recruited through the deciphering developmental disorders (DDD) study. Functional studies were undertaken using patient-specific Trio protein mutations.ResultsWe identified a frameshift deletion in TRIO that segregated autosomal dominantly. By scrutinising data from DDD, we further identified three unrelated children with a similar phenotype who harboured de novo missense mutations in TRIO. Biochemical studies demonstrated that in three out of four families, the Trio mutations led to a markedly reduced Rac1 activation.ConclusionsWe describe an inherited global developmental delay phenotype associated with a frameshift deletion in TRIO. Additionally, we identify pathogenic de novo missense mutations in TRIO associated with the same consistent phenotype, intellectual disability, microcephaly and dysmorphism with striking digital features. We further functionally validate the importance of the GEF domain in Trio protein function. Our study demonstrates how genomic technologies are yet again proving prolific in diagnosing and advancing the understanding of neurodevelopmental disorders.

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Section: Discussionsupporting

confidence: 89%

“…Our findings consolidate and extend the human phenotype recently reported by Ba et al 3. Through the application of parent/offspring WES analysis, we report three children from across the UK with microcephaly and neurodevelopmental delay who harbour de novo missense mutations in TRIO .…”

Section: Introductionsupporting

confidence: 89%

Mutations specific to the Rac-GEF domain ofTRIOcause intellectual disability and microcephaly

Pengelly¹,

Greville‐Heygate²,

Schmidt³

et al. 2016

J Med Genet

105

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“…Transfer the cover slips containing the hiPSC-derived neuronal cultures to a submerged fixed-stage recording chamber in an upright microscope. Record 20 min of spontaneous action potential-evoked postsynaptic currents (sEPSC) 24 . Detect the synaptic event using neuroscientific program.…”

Section: Establish the Neurophysiological Profile Of Hipsc-derived Nementioning

confidence: 99%

“…Characterize the neuronal morphology and synapsin expression 1. Fix and stain the hiPSC-derived neurons for MAP2, synapsin-1/2, and PSD-95 22,24,25 . Quantify the number of synapsin-1/2 and PSD-95 puncta using image analysis software.…”

Section: Establish the Neurophysiological Profile Of Hipsc-derived Nementioning

confidence: 99%

Rapid Neuronal Differentiation of Induced Pluripotent Stem Cells for Measuring Network Activity on Micro-electrode Arrays

Frega

Gestel

Linda

et al. 2017

JoVE

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107

177

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Neurons derived from human induced Pluripotent Stem Cells (hiPSCs) provide a promising new tool for studying neurological disorders. In the past decade, many protocols for differentiating hiPSCs into neurons have been developed. However, these protocols are often slow with high variability, low reproducibility, and low efficiency. In addition, the neurons obtained with these protocols are often immature and lack adequate functional activity both at the single-cell and network levels unless the neurons are cultured for several months. Partially due to these limitations, the functional properties of hiPSC-derived neuronal networks are still not well characterized. Here, we adapt a recently published protocol that describes production of human neurons from hiPSCs by forced expression of the transcription factor neurogenin-2 12. This protocol is rapid (yielding mature neurons within 3 weeks) and efficient, with nearly 100% conversion efficiency of transduced cells (>95% of DAPI-positive cells are MAP2 positive). Furthermore, the protocol yields a homogeneous population of excitatory neurons that would allow the investigation of celltype specific contributions to neurological disorders. We modified the original protocol by generating stably transduced hiPSC cells, giving us explicit control over the total number of neurons. These cells are then used to generate hiPSC-derived neuronal networks on micro-electrode arrays. In this way, the spontaneous electrophysiological activity of hiPSC-derived neuronal networks can be measured and characterized, while retaining interexperimental consistency in terms of cell density. The presented protocol is broadly applicable, especially for mechanistic and pharmacological studies on human neuronal networks.

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“…Of note, mutations in TRIO (MIM: 601893), a gene that encodes a RAC1 GEF, have been shown to result in mild intellectual disability. 43,44 Interestingly, missense mutations in RAC-GEF domain of TRIO result in a more severe phenotype with global developmental delay, microcephaly, and reduced RAC1 activity. 43 Furthermore, biallelic mutations in HACE1 (MIM: 610876), a known interactor of RAC1, have been recently shown to result in an autosomal-recessive syndrome with macrocephaly.…”

mentioning

confidence: 99%

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Reijnders

Ansor

Kousi

et al. 2017

The American Journal of Human Genetics

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124

141

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RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between À2.5 to À5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of þ4.16 and þ4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of $10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.Developmental disorders (DDs) are etiologically extremely heterogeneous and affect 2%-5% of individuals.

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TRIOloss of function is associated with mild intellectual disability and affects dendritic branching and synapse function

Cited by 89 publications

References 54 publications

Mutations specific to the Rac-GEF domain ofTRIOcause intellectual disability and microcephaly

Mutations specific to the Rac-GEF domain ofTRIOcause intellectual disability and microcephaly

Rapid Neuronal Differentiation of Induced Pluripotent Stem Cells for Measuring Network Activity on Micro-electrode Arrays

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

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