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Heterozygous variants in the mechanosensitive ion channel TMEM63A result in transient hypomyelination during infancy [article]

Huifang Yan, Guy Helman, Swetha Murthy, Haoran Ji, Joanna Crawford, Thomas Kubisiak, Stephen J. Bent, Jiangxi Xiao, Ryan J. Taft, Adam Coombs, Ye Wu, Ana Pop (+10 others)
2019 bioRxiv   pre-print

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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
more » ... n serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed 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 mechanically activated (MA) ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modelled variants result in strongly attenuated stretch-activated currents when expressed in naïve 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 four years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.
doi:10.1101/682179 fatcat:wqygg4dicnctrcuycguuxqpkiq
Citation

Huifang Yan, Guy Helman, Swetha 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 Salomons, Marjo S. van der Knaap, Ardem Patapoutian, Cas Simons, Margit Burmeister, Jingmin Wang, Nicole I. Wolf. "Heterozygous variants in the mechanosensitive ion channel TMEM63A result in transient hypomyelination during infancy." bioRxiv (2019)