RT Journal Article SR Electronic T1 Heterozygous variants in the mechanosensitive ion channel TMEM63A result in transient hypomyelination during infancy JF bioRxiv FD Cold Spring Harbor Laboratory SP 682179 DO 10.1101/682179 A1 Huifang Yan A1 Guy Helman A1 Swetha E. Murthy A1 Haoran Ji A1 Joanna Crawford A1 Thomas Kubisiak A1 Stephen J. Bent A1 Jiangxi Xiao A1 Ryan J. Taft A1 Adam Coombs A1 Ye Wu A1 Ana Pop A1 Dongxiao Li A1 Linda S. de Vries A1 Yuwu Jiang A1 Gajja S. Salomons A1 Marjo S. van der Knaap A1 Ardem Patapoutian A1 Cas Simons A1 Margit Burmeister A1 Jingmin Wang A1 Nicole I. Wolf YR 2019 UL http://biorxiv.org/content/early/2019/07/03/682179.abstract AB 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 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 results 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.