A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis

Yoneno, Shota; Yamamoto, Kaoru; Tabata, Kenshiro; Shimizu-Motohashi, Yuko; Tomita, Ayaka; Hayashi, Taiju; Maki, Hiroyuki; Sato, Noriko; Inoue, Ken; Saitsu, Hirotomo; Komaki, Hirofumi

doi:10.1038/s10038-024-01268-z

J Hum Genet

2024

DOI: 10.1038/s10038-024-01268-z

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A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis

Shota Yoneno,

Kaoru Yamamoto,

Kenshiro Tabata

et al.

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2024

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

Halford,

Senatore,

Berryman

et al. 2024

Preprint

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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 geneTMEM63Aencodes a mechanosensitive ion channel whose role in myelination has not been explored. Our study shows that TMEM63A is a major regulator of OL-driven myelination in the CNS. In mouse and zebrafish,Tmem63ainactivation led to early deficits in myelination, recapitulating the HLD19 phenotype. OL-specific conditional mouse knockouts ofTmem63aexhibited transient reductions in myelin, indicating that TMEM63A regulates myelination cell-autonomously. We show that TMEM63A is present at plasma membrane and on lysosomes and modulates myelin/myelin-associated protein production. Intriguingly, HLD19-associatedTMEM63Avariants from patients blocked trafficking to cell membrane. Together, our results reveal an ancient role for TMEM63A in fundamental aspects of myelinationin vivoand highlight two exciting new models for the development of treatments for devastating hypomyelinating leukodystrophies.

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

Halford,

Senatore,

Berryman

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis

Cited by 1 publication

References 13 publications

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

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

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