Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy

Huifang Yan, Guy Helman, Swetha E. Murthy, Haoran Ji, Joanna Crawford, Thomas Kubisiak, Stephen J. Bent, Jiangxi Xiao, Ryan J. Taft, Adam Coombs, Ye Wu, Ana Pop, Dongxiao Li, Linda S. de Vries, Yuwu Jiang, Gajja S. Salomons, Marjo S. van der Knaap, Ardem Patapoutian, Cas Simons, Margit BurmeisterJingmin Wang, Nicole I. Wolf

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)996-1004
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number5
StatePublished - Nov 7 2019
Externally publishedYes


  • MRI
  • TMEM63A
  • hypomyelination
  • leukodystrophy
  • mechanically activated (MA) ion channels
  • myelin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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