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In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
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Functional Study of TMEM163 Gene Variants Associated with Hypomyelination Leukodystrophy
Huifang Yan1,2,3,4, Shuyan Yang5, Yiming Hou6
1Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Cells
|April 23, 2022
Summary
Genetic variants in TMEM163, a zinc transporter, are linked to hypomyelinating leukodystrophies (HLDs). This study reveals TMEM163
Area of Science:
- Genetics
- Neuroscience
- Cell Biology
Background:
- Hypomyelinating leukodystrophies (HLDs) are rare genetic disorders causing myelin deficits.
- The genetic basis of many HLD cases remains unexplained.
- TMEM163, a zinc transporter, has not been previously linked to myelin development.
Purpose of the Study:
- To identify novel genes associated with unexplained hypomyelinating leukodystrophies.
- To investigate the role of TMEM163 variants in HLD pathogenesis.
Main Methods:
- Trio-based whole exome sequencing in HLD patients.
- Functional studies using HeLa cells to assess zinc transport.
- Zebrafish model (morphants) for in vivo validation of TMEM163 function.
Main Results:
- Two de novo heterozygous variants in TMEM163 (p.(L76R) and p.(L76P)) were identified in two unrelated HLD patients.
- TMEM163 variants altered zinc efflux function in vitro.
- Zebrafish lacking TMEM163 exhibited myelin deficits, developmental abnormalities, and motor impairment; human wild-type TMEM163 rescued the phenotype, while mutants exacerbated it.
- Oligodendrocyte and neuron development were negatively impacted in zebrafish morphants.
Conclusions:
- TMEM163 plays a crucial, previously unrecognized role in myelin development.
- TMEM163 variants are associated with hypomyelinating leukodystrophy.
- This study expands the genetic landscape of HLDs.
