TMEM63A, associated with hypomyelinating leukodystrophies, is an evolutionarily conserved regulator of myelination.

Infantile hypomyelinating leukodystrophy 19 (HLD19) is a rare genetic disorder where patients exhibit reduced myelin in central nervous system (CNS) white matter tracts and present with varied neurological symptoms. The causative gene TMEM63A encodes a mechanosensitive ion channel whose role in myelination is largely unexplored. Our study shows that TMEM63A is a major regulator of oligodendrocyte (OL)-dependent myelination in the CNS. In mouse and zebrafish, Tmem63a inactivation led to early deficits in myelination, recapitulating the HLD19 phenotype. OL-specific conditional mouse knockouts of Tmem63a exhibited transient reductions in myelin, indicating that TMEM63A regulates myelination cell-autonomously. We show that TMEM63A is present at the plasma membrane and on lysosomes and modulates myelin production in the presence of mechanical cues. Intriguingly, HLD19-associated TMEM63A variants from patients blocked trafficking to cell membrane. Together, our results reveal an ancient role for TMEM63A in fundamental aspects of myelination in vivo and highlight two exciting models for the development of treatments for devastating hypomyelinating leukodystrophies.