• syndrome

TBC1D24-related disorders comprise group of diseases, sometimes described as a continuum rather than distinct diseases, characterized by some combination of deafness, epilepsy and seizures, or intellectual disability; other phenotypes may be present. See the OMIM report for TBC1D24 (MIM:613577) and corresponding disease links. Most of the diseases associated with TBC1D24 exhibit autosomal recessive inheritance. As its full name indicates, TBC1D24 (TBC1 domain family member 24) encodes a protein with a TBC domain; it may serve as a GTPase-activating protein for Rab small GTPases, which are involved in the regulation of membrane trafficking. There is a single orthologous gene in Drosophila, Dmel\sky, for which loss-of-function mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Multiple UAS constructs of the human Hsap\TBC1D24 gene have been introduced into flies, including wild-type and variants implicated in disease. The Hsap\TBC1D24 wild-type gene exhibits heterologous rescue (functional complementation) for the lethality observed for loss-of-function mutations of Dmel\sky.

Animals homozygous for severe loss-of-function alleles of Dmel\sky die during the embryonic or early larval stages. Less severe alleles survive to the pupal stage; neurophysiology defects are observed in larvae. Abnormalities are observed in endosomal-to-lysosomal synaptic vesicle trafficking. Animals carrying a transgenic sky allele corresponding to a DOORS-implicated variant exhibit locomotor defects and a bang-sensitive (epileptic-like) phenotype. Physical and genetic interactions of Dmel\sky have been described; see below and in the sky gene report.

Variant(s) implicated in human disease tested (as transgenic human gene, TBC1D24): the R40C variant (implicated in DOORS syndrome), the G501R variant (implicated rolandic epilepsy), and the R360H variant (implicated rolandic epilepsy) have been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R79C in the fly sky gene (corresponds to R40C in the human TBC1D24 gene, implicated in DOORS syndrome); R281C in the fly sky gene (corresponds to R242C in the human TBC1D24 gene, implicated in DOORS syndrome).

See the human disease model reports 'DOORS syndrome' (FBhh0000720) and 'epilepsy, rolandic, with paroxysmal exercise-induced dystonia' (FBhh0001132).

[updated Feb. 2020 by FlyBase; FBrf0222196]