ArticleBrain : a journal of neurology2022
Variants in the zinc transporter TMEM163 cause a hypomyelinating leukodystrophy.
Article in Brain : a journal of neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 18 citations in OpenAlex.
- A Genome-wide Association Study of Alzheimer's Disease and Dementia in a Large Multi-ancestry Military Cohort Identifies Many New Dementia-Associated Loci.medRxiv : the preprint server for health sciences · 2026Article
- Interleukin-4-Enhanced Oligodendrocyte Differentiation Depends on Extracellular Zinc Uptake via ZIP11.Cells · 2025Article
- Assessment the Efficacy of the CRISPR System for Inducing Mutations in the AIMP2 Gene to Create a Cell Line Model of HLD17 Disease.Molecular biotechnology · 2025Article
- An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.Nature communications · 2025Article
- SLC30 (ZnT) and SLC39 (ZIP) zinc transporter families: from gatekeepers of zinc homeostasis to promoters of tumorigenesis and targets for clinical therapy.Frontiers in immunology · 2025Review
- Biallelic EPB41L3 variants underlie a developmental disorder with seizures and myelination defects.Brain : a journal of neurology · 2024Article
- BayesKAT: bayesian optimal kernel-based test for genetic association studies reveals joint genetic effects in complex diseases.Briefings in bioinformatics · 2024Article
- Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- Neurodevelopmental Consequences of Dietary Zinc Deficiency: A Status Report.Biological trace element research · 2023Review
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Authors and funding
18 authors at 7 institutions in 3 countries.
Funding
Abstract
Hypomyelinating leukodystrophies comprise a subclass of genetic disorders with deficient myelination of the CNS white matter. Here we report four unrelated families with a hypomyelinating leukodystrophy phenotype harbouring variants in TMEM163 (NM_030923.5). The initial clinical presentation resembled Pelizaeus-Merzbacher disease with congenital nystagmus, hypotonia, delayed global development and neuroimaging findings suggestive of significant and diffuse hypomyelination. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant. TMEM163 is highly expressed in the CNS particularly in newly myelinating oligodendrocytes and was recently revealed to function as a zinc efflux transporter. All the variants identified lie in highly conserved residues in the cytoplasmic domain of the protein, and functional in vitro analysis of the mutant protein demonstrated significant impairment in the ability to efflux zinc out of the cell. Expression of the mutant proteins in an oligodendroglial cell line resulted in substantially reduced mRNA expression of key myelin genes, reduced branching and increased cell death. Our findings indicate that variants in TMEM163 cause a hypomyelinating leukodystrophy and uncover a novel role for zinc homeostasis in oligodendrocyte development and myelin formation.
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