Langhammer, F., Gregor, A., Ntamati, N.R., Ekici, A.B., Winner, B., Nevian, T., Zweier, C. (2025). Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy.  Hum. Mol. Genet. 34(7): 639--650.

FBrf0261941

Research paper

While de novo missense variants in the BTB domains of atypical RhoGTPase RHOBTB2 cause a severe developmental and epileptic encephalopathy, de novo missense variants in the GTPase domain or bi-allelic truncating variants are associated with more variable neurodevelopmental and seizure phenotypes. Apart from the observation of RHOBTB2 abundance resulting from BTB-domain variants and increased seizure susceptibility in Drosophila overexpressing RhoBTB, our knowledge on RHOBTB2-related pathomechanisms is limited. We now found enrichment for ion channels among the differentially expressed genes from RNA-Seq on fly heads overexpressing RhoBTB. Subsequent genetic interaction experiments confirmed a functional link between RhoBTB and paralytic, the orthologue of human sodium channels, including epilepsy associated SCN1A, in vivo. We then performed patch-clamp recordings on mature neurons differentiated from human induced pluripotent stem cells with either homozygous frameshifts or patient-specific heterozygous missense variants in the GTPase or the BTB domains. This revealed significantly altered neuronal activity and excitability resulting from BTB domain variants but not from GTPase domain variants or upon complete loss of RHOBTB2. Our study indicates a role of deregulated ion channels in the pathogenesis of RHOBTB2-related developmental and epileptic encephalopathy and points to specific pathomechanisms underlying the observed genotype-phenotype correlations regarding variant zygosity, location and nature.

PMC11924187 (PMC) (EuropePMC)