ArticleAmerican journal of human genetics2019
Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy.
Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 90 citations in OpenAlex.
- Lipid flip-flop in biological membranes: through the lens of TMEM16F.Physiological reviews · 2027Review
- A TMEM63B variant with enhanced mechanosensitive channel activity and acquired lipid scramblase function.The Journal of general physiology · 2026Article
- Ion transport as a determinant of membrane fusion and fission.Nature structural & molecular biology · 2026Review
- NovelWorld journal of clinical pediatrics · 2026Article
- Opening threshold and kinetics of the MscL mechanosensitive channel are regulated by its periplasmic loop.Research square · 2026Article
- PIEZOs regulate oligodendrocyte sheath formation, expansion, and myelination potential.bioRxiv : the preprint server for biology · 2026Article
- TMEM63 proteins act as mechanically activated cholesterol modulated lipid scramblases contributing to membrane mechano-resilience.Nature communications · 2026Article
- Opening threshold and kinetics of the MscL mechanosensitive channel are regulated by its periplasmic loop.npj biological physics and mechanics · 2026Article
- Mechanosensitive TMEM63 Ion Channels: Structure, Gating Mechanism, and Emerging Physiological and Pathological Roles.Results and problems in cell differentiation · 2026Review
- From plasma membrane to lysosomes: expanding roles of TMEM63/OSCA channels in mechanosensation and intracellular signaling.Frontiers in pharmacology · 2026Review
- Glial Ion Channels in Myelin Pathophysiology: Insights from Leukodystrophies.Life (Basel, Switzerland) · 2025Review
- Piezo1 in microglial cells: Implications for neuroinflammation and tumorigenesis.Channels (Austin, Tex.) · 2025Review
- Spatial lipidomics reveals altered lipid profiles in TMEM63A mutant rats with hypomyelination.Scientific reports · 2025Article
- Article
- Lysosomal ion channels and pain.Pain reports · 2025Review
- TMEM63A, associated with hypomyelinating leukodystrophies, is an evolutionarily conserved regulator of myelination.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Unnatural Amino Acid Photo-Crosslinking Sheds Light on Gating of the Mechanosensitive Ion Channel OSCA1.2.International journal of molecular sciences · 2025Article
- Overview of genetic variants in a cohort of Iranian patients with leukodystrophy.Scientific reports · 2025Article
- Cation Channel TMEM63A Autonomously Facilitates Oligodendrocyte Differentiation at an Early Stage.Neuroscience bulletin · 2025Article
- Wide-ranging cellular functions of ion channels and lipid scramblases in the structurally related TMC, TMEM16 and TMEM63 families.Nature structural & molecular biology · 2025Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
22 authors at 14 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed that all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a MA ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modeled variants result in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after 4 years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.
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