Cross-species analysis of GNB1 I80T encephalopathy: conserved developmental, epileptic and neuronal transcriptome signatures

Abstract

GNB1 encephalopathy (GNB1E) is a rare neurodevelopmental disorder caused by mutations in GNB1 gene encoding the G protein subunit G{beta}1. Mechanisms linking these variants to neurological dysfunction remain unclear. We investigated the prevalent p.Ile80Thr (I80T) variant using combined clinical, cellular, and in vivo approaches. Longitudinal evaluation of a GNB1E patient revealed developmental delay, progressive peripheral spasticity, and epilepsy with Spike-Wave Activation in Sleep. Heterozygous knock-in Gnb1I80T/+ mice exhibited disease-relevant phenotypes, including impaired early development, mild adult motor and cognitive deficits and epileptiform cortical spike-and-wave discharges. Transcriptomic analysis identified 323 genes concordantly dysregulated in mouse cortex and cortical human neuronal cultures from patient-derived induced pluripotent cells. This gene set was enriched for ion-channel function, epilepsy-associated genes, and Gs/adenylyl cyclase signaling pathway. Our integrated analysis establishes the first cross-species model for GNB1E, suggests common neurological mechanisms and molecular pathways linked to GNB1E, and provides a framework for mechanistic and therapeutic studies. TeaserConserved human/mouse neurological and transcriptomic signatures in GNB1 encephalopathy.