RAC1 – MRD48 (intellectual disability, autosomal dominant 48)

RAC1 is a small Rho GTPase involved in actin cytoskeleton remodeling, cell migration and differentiation. Heterozygous de novo missense variants in RAC1 have been causally linked to MRD48, a neurodevelopmental disorder characterized by developmental delay, intellectual disability and brain structural abnormalities. RAC1 – intellectual disability, autosomal dominant 48

Genetic evidence supports autosomal dominant inheritance. Two unrelated probands with novel de novo RAC1 missense variants exhibited global developmental delay and variable brain anomalies ([PMID:37059841]). No familial segregation beyond the probands has been reported, consistent with a de novo mechanism.

All reported pathogenic RAC1 variants in MRD48 are missense, clustering in domains critical for GTP binding and hydrolysis. These GoF variants result in increased downstream signaling without loss-of-function. So far no loss-of-function or truncating variants have been associated with MRD48.

Functional studies demonstrate that patient-derived RAC1 missense mutations produce a constitutively active (gain-of-function) phenotype. In vitro GTPase assays and structural modeling showed enhanced GTP binding and effector interaction, recapitulating the neurodevelopmental phenotype in neuronal assays ([PMID:37059841]).

Mechanistically, RAC1 GoF leads to aberrant actin dynamics in neural progenitors and disrupted neuronal migration. These findings were consistent across structural, biochemical and cellular models, supporting a dominant gain-of-function pathogenic mechanism.

Given the strong de novo genetic evidence and concordant functional data, RAC1 variant testing should be included in neurodevelopmental genetic panels, and functional characterization of novel variants is critical for diagnosis and prognosis.

References

• European journal of human genetics • 2023 • Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants. PMID:37059841

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