Pathogenic variants in TMEM184B cause a neurodevelopmental syndrome associated with alteration of metabolic signaling.

Transmembrane protein 184B (TMEM184B) is an endosomal 7-pass transmembrane protein with evolutionarily conserved roles in synaptic structure and axon degeneration. We report six pediatric cases who have de novo heterozygous variants in TMEM184B; five individuals harbor a rare missense variant and one individual has an mRNA splice site change. This cohort is unified by overlapping neurodevelopmental deficits including developmental delay, corpus callosum hypoplasia, seizures, and/or microcephaly. TMEM184B is predicted to contain a pore domain wherein four of five human disease-associated missense variants cluster. Structural modeling suggests that all missense variants alter TMEM184B protein stability. To understand the contribution of TMEM184B to neural development in vivo, we knocked down the TMEM184B ortholog in zebrafish and observed microcephaly and reduced anterior commissural axons, aligning with symptoms of affected individuals. Ectopic expression of TMEM184B c.550A>G; p.Lys184Glu and c.484G>A; p.Gly162Arg variants cause reduced head size and body length, indicating dominant effects, while three other variants show haploinsufficiency. None of the variants are able to rescue the knockdown phenotype. Human induced pluripotent stem cells (iPSC) with monoallelic production of p.Lys184Glu show mRNA disruptions in key metabolic pathways including those controlling mechanistic target of rapamycin (mTOR) activity. Expression of p.Lys184Glu and c.863G>C; p.Gly288Ala increased apoptosis in cell lines and p.Lys184Glu increased nuclear localization of transcription factor EB (TFEB), consistent with a cellular starvation state. Together, our data indicate that TMEM184B variants cause cellular metabolic disruption and result in abnormal neural development.