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

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.

Distant coupling between RNA editing and alternative splicing of the osmosensitive cation channel Tmem63b

“…Recently, the osmosensitive cation channels in TMEM63 family have attracted research interests ( 27 , 28 , 29 ). When analyzing Tmem63b cDNAs from mouse brain tissues, we obtained one cDNA sequence that was different from the documented mRNA sequence NM_198167 in the NCBI database ( Fig.…”

The CNS Myelin Proteome: Deep Profile and Persistence After Post-mortem Delay

“…For newly identified disease genes, thus, evaluating mRNA-expression using transcriptome datasets and presence of the protein in myelin using the present myelin proteome resource may serve as a useful entry point into identifying the primarily affected cell type. For example, mutations of the HSPD1 gene cause HLD4 or SPG13 ( Hansen et al, 2002 ; Magen et al, 2008 ) and mutations of the TMEM63A gene cause HLD19 ( Yan et al, 2019 ) ( Table 1 ). Considering that both transcripts are expressed in oligodendrocytes as per transcriptome datasets and both proteins are comprised in the myelin proteome, the disease mechanisms may involve primary impairment of the biogenesis, maintenance or functions of myelin.…”

Mechanobiology of the brain in ageing and Alzheimer's disease

“…Recent observations by others also suggest that OPC maturation is, in part, regulated by mechanosensitive Piezo1 channels (Segel et al., 2019). Interestingly, missense mutations in a gene known as TMEM63A, which encodes for a mechanosensitive ion channel that is highly expressed in oligodendrocytes, result in a transient infantile disorder in humans that resembles a hypomyelinating leukodystrophy, which somehow resolves within the first 4 years of life (Yan et al., 2019). These and other studies (Espinosa‐Hoyos et al., 2018; Jagielska et al., 2017; Mei et al., 2014) point towards an important role for mechanosensation in developmental myelin formation in the brain.…”