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Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental
Sónia Barbosa1, Stephanie Greville-Heygate2, Maxime Bonnet1
1Centre de Recherche en Biologie Cellulaire de Montpellier, University of Montpellier, Centre National de la Recherche Scientifique 34293 Montpellier, France.
Pathogenic variants in the TRIO gene cause neurodevelopmental disorders. Specific TRIO mutations lead to distinct intellectual disability severity and head size variations by altering RAC1 signaling.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- TRIO (Rho-guanine nucleotide exchange factor) is crucial for neuronal development, regulating migration, outgrowth, guidance, and synaptogenesis via RAC1 activation and actin remodeling.
- Pathogenic TRIO variants are linked to neurodevelopmental disorders like intellectual disability (ID) and autism spectrum disorders (ASD).
Purpose of the Study:
- To investigate the clinical and molecular spectrum of TRIO-related neurodevelopmental disorders.
- To correlate specific TRIO variant locations with distinct phenotypic presentations and RAC1 signaling alterations.
Main Methods:
- Analysis of the largest international cohort (24 individuals) with confirmed pathogenic TRIO variants (missense and nonsense).
- Genomic sequencing to identify TRIO variants.
- Clinical phenotyping, including neurodevelopmental assessments and head circumference measurements.
- Functional studies in human cells and the model organism X. tropicalis to assess RAC1 activation and cellular defects.
Main Results:
- Nonsense mutations in TRIO showed variable neurodevelopmental phenotypes.
- Missense variants clustered in the spectrin repeat 7 and GEFD1 domains, correlating with distinct clinical outcomes.
- Spectrin repeat 7 variants were associated with more severe ID and macrocephaly.
- GEFD1 variants were linked to milder ID and microcephaly.
- Functional studies revealed TRIO variants cause either hyper- or hypo-activation of RAC1, with a strong correlation between RAC1 activity levels and head size.
- X. tropicalis models with TRIO GEFD1 truncations recapitulated human phenotypes.
Conclusions:
- Distinct clinical and molecular disorders are associated with variants in the TRIO GEFD1 and spectrin repeat 7 domains.
- Precise regulation of TRIO-RAC1 signaling is essential for normal neuronal development.
- TRIO variants represent a significant genetic cause of neurodevelopmental disorders with genotype-phenotype correlations.
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