• central nervous system disease

This report describes a Drosophila model of TMEM63-associated neurological disorders using the orthologous fly gene Tmem63. There are three human genes in this family of mechanosensitive ion channels: TMEM63A, which is implicated in hypomyelinating leukodystrophy 19 (MIM:618688); TMEM63C, which is implicated in spastic paraplegia 87 (MIM:619966); and TMEM63B, which has been tentatively implicated in developmental and epileptic encephalopathy (see FBhh0001531).

All three human genes, Hsap\TMEM63A, Hsap\TMEM63B, and Hsap\TMEM63C, have been introduced into flies. Characterization of Hsap\TMEM63B in the context of a Drosophila disease model is described in a separate human disease model report (FBhh0001531).

Extensive work in flies involves characterization of the role of the Tmem63 protein as a mechanosensor localized to the lysosome membrane.

Animals homozygous for loss-of-function Tmem63 mutations are viable and fertile, but exhibit reduced lifespan and progressive motor impairment with age; they also exhibit progressive synaptic loss (assayed in the adult neuromuscular junction) and impaired lysosomal activity.

A mutation of Tmem63 analogous to a disease-implicated variant of TMEM63A has been created and characterized. The mutant Tmem63 protein is mislocalized to the endoplasmic reticulum and fails to rescue the motor deficits of loss-of-function Tmem63 mutant flies. See the 'Disease-Implicated Variants' table below.

[updated Jun. 2024 by FlyBase; FBrf0222196]