PUBLICATION

Functional Study of TMEM163 Gene Variants Associated with Hypomyelination Leukodystrophy

Authors
Yan, H., Yang, S., Hou, Y., Ali, S., Escobar, A., Gao, K., Duan, R., Kubisiak, T., Wang, J., Zhang, Y., Xiao, J., Jiang, Y., Zhang, T., Wu, Y., Burmeister, M., Wang, Q., Cuajungco, M.P., Wang, J.
ID
ZDB-PUB-220424-9
Date
2022
Source
Cells   11(8): (Journal)
Registered Authors
Wang, Qiang, Zhang, Yu
Keywords
TMEM163 protein, hypomyelination leukodystrophy, zinc efflux transporter
MeSH Terms
  • Animals
  • Demyelinating Diseases*/metabolism
  • HeLa Cells
  • Humans
  • Lysosomal Storage Diseases*/metabolism
  • Membrane Proteins*/genetics
  • Membrane Proteins*/metabolism
  • Myelin Sheath/genetics
  • Myelin Sheath/metabolism
  • Neurodegenerative Diseases*/metabolism
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zinc/metabolism
PubMed
35455965 Full text @ Cells
Abstract
Hypomyelinating leukodystrophies (HLDs) are a rare group of heterogeneously genetic disorders characterized by persistent deficit of myelin observed on magnetic resonance imaging (MRI). To identify a new disease-associated gene of HLD, trio-based whole exome sequencing was performed for unexplained patients with HLD. Functional studies were performed to confirm the phenotypic effect of candidate protein variants. Two de novo heterozygous variants, c.227T>G p.(L76R) or c.227T>C p.(L76P) in TMEM163 were identified in two unrelated HLD patients. TMEM163 protein is a zinc efflux transporter localized within the plasma membrane, lysosomes, early endosomes, and other vesicular compartments. It has not been associated with hypomyelination. Functional zinc flux assays in HeLa cells stably-expressing TMEM163 protein variants, L76R and L76P, revealed distinct attenuation or enhancement of zinc efflux, respectively. Experiments using a zebrafish model with knockdown of tmem163a and tmem163b (morphants) showed that loss of tmem163 causes dysplasia of the larvae, locomotor disability and myelin deficit. Expression of human wild type TMEM163 mRNAs in morphants rescues the phenotype, while the TMEM163 L76P and L76R mutants aggravated the condition. Moreover, poor proliferation, elevated apoptosis of oligodendrocytes, and reduced oligodendrocytes and neurons were also observed in zebrafish morphants. Our findings suggest an unappreciated role for TMEM163 protein in myelin development and add TMEM163 to a growing list of genes associated with hypomyelination leukodystrophy.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping