Pathogenic variants inTMEM184Bcause a neurodevelopmental syndrome via alteration of metabolic signaling

Abstract

ABSTRACTTransmembrane protein 184B (TMEM184B) is an endosomal 7-pass transmembrane protein with evolutionarily conserved roles in synaptic structure and axon degeneration. We report six pediatric patients who havede novoheterozygous variants inTMEM184B. All individuals harbor rare missense or mRNA splicing changes and have neurodevelopmental deficits including intellectual disability, corpus callosum hypoplasia, seizures, and/or microcephaly. TMEM184B is predicted to contain a pore domain, wherein many human disease-associated variants cluster. Structural modeling suggests that all missense variants alter TMEM184B protein stability. To understand the contribution of TMEM184B to neural developmentin vivo, we suppressed the TMEM184B ortholog in zebrafish and observed microcephaly and reduced anterior commissural neurons, aligning with patient symptoms. EctopicTMEM184Bexpression resulted in dominant effects for K184E and G162R. However,in vivocomplementation studies demonstrate that all other variants tested result in diminished protein function and indicate a haploinsufficiency basis for disease. Expression of K184E and other variants increased apoptosis in cell lines and altered nuclear localization of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, suggesting disrupted nutrient signaling pathways. Together, our data indicate that TMEM184B variants cause cellular metabolic disruption likely through divergent molecular effects that all result in abnormal neural development.