TY - JOUR
T1 - Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy
AU - Yan, Huifang
AU - Helman, Guy
AU - Murthy, Swetha E.
AU - Ji, Haoran
AU - Crawford, Joanna
AU - Kubisiak, Thomas
AU - Bent, Stephen J.
AU - Xiao, Jiangxi
AU - Taft, Ryan J.
AU - Coombs, Adam
AU - Wu, Ye
AU - Pop, Ana
AU - Li, Dongxiao
AU - de Vries, Linda S.
AU - Jiang, Yuwu
AU - Salomons, Gajja S.
AU - van der Knaap, Marjo S.
AU - Patapoutian, Ardem
AU - Simons, Cas
AU - Burmeister, Margit
AU - Wang, Jingmin
AU - Wolf, Nicole I.
N1 - Copyright © 2019 American Society of Human Genetics. All rights reserved.
PY - 2019/11/7
Y1 - 2019/11/7
N2 - 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.
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 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.
KW - MRI
KW - TMEM63A
KW - hypomyelination
KW - leukodystrophy
KW - mechanically activated (MA) ion channels
KW - myelin
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UR - https://www.ncbi.nlm.nih.gov/pubmed/31587869
U2 - https://doi.org/10.1016/j.ajhg.2019.09.011
DO - https://doi.org/10.1016/j.ajhg.2019.09.011
M3 - Article
C2 - 31587869
SN - 0002-9297
VL - 105
SP - 996
EP - 1004
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -