Journal article
Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1
European journal of human genetics : EJHG
12 May 2026
PMID: 42120539
Abstract
RAC1 is a signal transducer essential for neurodevelopment. Missense variants in RAC1 cause heterogeneous neurodevelopmental disorders whose features include intellectual disability and developmental delay. Individuals with RAC1 variants are categorized by head circumference into microcephalic, normocephalic and macrocephalic groups. We previously described a cohort of individuals with variants affecting the N-terminal part (Q61-R68) of switch II, a functional domain of RAC1. This cohort was normocephalic and their variants increased RAC1 signalling activity. Here, we report 15 new individuals with variants in switch II of RAC1. We describe clinical features for two individuals with variants affecting the N-terminal part of switch II (Q61-R68) and four individuals with variants in its C-terminal part (P69-Q74). All individuals exhibit intellectual disabilities and neuroradiological anomalies. Consistent with our previous study, individuals with variants in the N-terminal part of switch II were normocephalic. By contrast, individuals with variants in the C-terminal part of switch II exhibited microcephaly. Cell-based assays revealed that N- and C-terminal variants affect RAC1 function differently: N-terminal variants are activating, while C-terminal variants are dominant-negative. In a Drosophila model, we observe divergent effects on neuronal morphology, with switch II N-terminal variants increasing the complexity of dendritic arbors, while switch II C-terminal variants reduce dendritic complexity. Switch II N-terminal variants increase locomotor activity of adult Drosophila, while C-terminal variants had minimal effect, suggesting diverging effects on neuronal function and behaviour. We conclude that variants affecting N- and C-terminal parts of RAC1 switch II cause phenotypically and mechanistically distinct disorders.
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Details
- Title
- Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1
- Creators
- Hebah O Althebaiti - University of ManchesterJames Cooksedge - Cancer Research UK Manchester InstituteMartin J Baker - Cancer Research UK Manchester InstituteMadeleine Smith - University of ManchesterVerity Edwards-Scott - University of ManchesterAndré Luiz Santos Pessoa - Universidade Federal do CearáHenri Margot - Centre Hospitalier Universitaire de BordeauxKay A Metcalfe - Manchester Academic Health Science CentreMélanie Fradin - Centre Hospitalier Universitaire de RennesHailey Mostow - St. Christopher's Hospital for ChildrenMarielle Alders - Institut de Médecine de la ReproductionPhillis Lakeman - University of ManchesterAngeliki Malliri - Cancer Research UK Manchester InstituteSiddharth Banka - Manchester Academic Health Science CentreTom H Millard - Manchester Academic Health Science Centre
- Publication Details
- European journal of human genetics : EJHG
- Publisher
- Nature Publishing
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine
- Web of Science ID
- WOS:001764128700001
- Scopus ID
- 2-s2.0-105038584485
- Other Identifier
- 991022197018804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity