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Updated: May 14, 2026
06:41
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1
Hebah O Althebaiti1,2, James Cooksedge3, Martin J Baker3
1Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
European Journal of Human Genetics : EJHG
|May 12, 2026
Summary
Variants in RAC1 switch II cause distinct neurodevelopmental disorders. N-terminal variants lead to normocephaly and increased signaling, while C-terminal variants cause microcephaly and dominant-negative effects, impacting neuronal development differently.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Rac GTPase (RAC1) is crucial for neurodevelopment.
- RAC1 variants cause neurodevelopmental disorders with varying head circumferences.
- Previous studies linked N-terminal switch II RAC1 variants to normocephaly and increased signaling.
Purpose of the Study:
- To investigate the clinical and mechanistic distinctions between N-terminal and C-terminal RAC1 switch II variants.
- To characterize new individuals with RAC1 switch II variants.
Main Methods:
- Clinical assessment of 15 new individuals with RAC1 switch II variants.
- Cell-based assays to determine RAC1 signaling activity.
- Drosophila models to assess neuronal morphology and behavior.
Main Results:
- N-terminal switch II variants are associated with normocephaly, increased RAC1 signaling, and enhanced dendritic complexity in Drosophila.
- C-terminal switch II variants are linked to microcephaly, dominant-negative RAC1 effects, and reduced dendritic complexity in Drosophila.
- Both N- and C-terminal variants cause intellectual disability and neuroradiological anomalies.
Conclusions:
- RAC1 switch II variants result in phenotypically and mechanistically distinct neurodevelopmental disorders.
- N-terminal variants activate RAC1, while C-terminal variants act in a dominant-negative manner.
- These findings highlight the differential impact of RAC1 switch II region variants on neurodevelopment.
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