PUBLICATION
Pathogenic variants in TMEM184B cause a neurodevelopmental syndrome associated with alteration of metabolic signaling
- Authors
- Chapman, K.A., Ullah, F., Yahiku, Z.A., Khan, S., Kodiparthi, S.V., Kellaris, G., White, H.G., Powell, A.T., Correia, S.P., Stödberg, T., Sofocleous, C., Marinakis, N.M., Fryssira, H., Tsoutsou, E., Traeger-Synodinos, J., Accogli, A., Sciruicchio, V., Salpietro, V., Striano, P., Muss, C., Keren, B., Heron, D., Berger, S.I., Pond, K.W., Sirimulla, S., Davis, E.E., Bhattacharya, M.R.C.
- ID
- ZDB-PUB-250831-3
- Date
- 2025
- Source
- American journal of human genetics : (Journal)
- Registered Authors
- Davis, Erica
- Keywords
- TFEB, corpus callosum, dominant toxic, epilepsy, haploinsufficiency, lysosome, microcephaly, neurodevelopment, transmembrane protein, zebrafish
- MeSH Terms
-
- Microcephaly/genetics
- Child, Preschool
- Male
- Membrane Proteins*/chemistry
- Membrane Proteins*/genetics
- Membrane Proteins*/metabolism
- Signal Transduction*/genetics
- Mutation, Missense/genetics
- Child
- Female
- Humans
- Zebrafish/genetics
- Neurodevelopmental Disorders*/genetics
- Neurodevelopmental Disorders*/metabolism
- Neurodevelopmental Disorders*/pathology
- Animals
- Infant
- PubMed
- 40885185 Full text @ Am. J. Hum. Genet.
Citation
Chapman, K.A., Ullah, F., Yahiku, Z.A., Khan, S., Kodiparthi, S.V., Kellaris, G., White, H.G., Powell, A.T., Correia, S.P., Stödberg, T., Sofocleous, C., Marinakis, N.M., Fryssira, H., Tsoutsou, E., Traeger-Synodinos, J., Accogli, A., Sciruicchio, V., Salpietro, V., Striano, P., Muss, C., Keren, B., Heron, D., Berger, S.I., Pond, K.W., Sirimulla, S., Davis, E.E., Bhattacharya, M.R.C. (2025) Pathogenic variants in TMEM184B cause a neurodevelopmental syndrome associated with alteration of metabolic signaling. American journal of human genetics. :.
Abstract
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 with monoallelic production of p.Lys184Glu show mRNA disruptions in key metabolic pathways including those controlling mechanistic target of rapamycin 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, consistent with a cellular starvation state. Together, our data indicate that TMEM184B variants cause cellular metabolic disruption and result in abnormal neural development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping