Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/122916
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Type: Journal article
Title: Heterozygous variants in the mechanosensitive ion channel TMEM63A result in transient hypomyelination during infancy
Author: Yan, H.
Helman, G.
Murthy, S.E.
Ji, H.
Crawford, J.
Kubisiak, T.
Bent, S.J.
Xiao, J.
Taft, R.J.
Coombs, A.
Wu, Y.
Pop, A.
Li, D.
de Vries, L.S.
Jiang, Y.
Salomons, G.S.
van der Knaap, M.S.
Patapoutian, A.
Simons, C.
Burmeister, M.
et al.
Citation: American Journal of Human Genetics, 2019; 105(5):996-1004
Publisher: Elsevier
Issue Date: 2019
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
Huifang Yan, Guy Helman, Swetha E.Murthy, Haoran Ji, Joanna Crawford
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.
Keywords: MRI
TMEM63A
hypomyelination
leukodystrophy
mechanically activated (MA) ion channels
myelin
Rights: © 2019 American Society of Human Genetics.
DOI: 10.1016/j.ajhg.2019.09.011
Grant ID: http://purl.org/au-research/grants/nhmrc/1068278
Published version: http://dx.doi.org/10.1016/j.ajhg.2019.09.011
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