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Variants in the zinc transporter TMEM163 cause a hypomyelinating leukodystrophy
Michelle C do Rosario1, Guillermo Rodriguez Bey2, Bruce Nmezi2
1Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
Brain : a Journal of Neurology
|August 11, 2022
Summary
Genetic variants in TMEM163 cause hypomyelinating leukodystrophy, a disorder affecting central nervous system (CNS) myelination. This research highlights the crucial role of zinc transport in oligodendrocyte development and myelin formation.
Area of Science:
- Neurogenetics
- Cellular Biology
- Developmental Neuroscience
Background:
- Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelination in the CNS.
- Pelizaeus-Merzbacher disease is a related condition with similar initial clinical symptoms.
Purpose of the Study:
- To investigate the genetic basis of a hypomyelinating leukodystrophy phenotype in four unrelated families.
- To elucidate the role of the TMEM163 gene and zinc homeostasis in central nervous system myelination.
Main Methods:
- Genomic testing to identify variants in the TMEM163 gene.
- In vitro functional analysis of mutant TMEM163 proteins to assess zinc efflux capabilities.
- Expression studies in an oligodendroglial cell line to evaluate the impact on myelin gene expression and cell viability.
Main Results:
- Identified three distinct heterozygous missense variants in TMEM163 in affected individuals.
- Demonstrated impaired zinc efflux function of the mutant TMEM163 proteins.
- Observed reduced myelin gene expression, decreased branching, and increased cell death in oligodendrocytes expressing mutant TMEM163.
Conclusions:
- Variants in TMEM163 are a cause of hypomyelinating leukodystrophy.
- Zinc homeostasis is essential for oligodendrocyte development and myelin formation.
- TMEM163 plays a critical role in maintaining CNS myelination.
