This report describes DOORS syndrome, which is one of several diseases associated with the human gene TBC1D24; DOORS syndrome exhibits 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. Variant(s) implicated in human disease tested (as transgenic human gene, TBC1D24): the G501R, R360H, and R40C variant forms of the human gene have been introduced into flies. Using the most severe mutation, G501R, pharmaceutical intervention has been assessed.
The crystal structure of the TBC domain of the Drosophila sky protein has been determined, revealing a cationic pocket conserved among TBC1D24 homologs. Several disease-implicated variants map to this region of the protein. Based on in vitro analyses of sky proteins with disease-implicated variants, it is postulated that membrane binding via this pocket restricts diffusion the sky protein in presynaptic terminals. Animals carrying a transgenic sky allele corresponding to a DOORS-implicated variant exhibit locomotor defects and a bang-sensitive (epileptic-like) phenotype. 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); R281C in the fly sky gene (corresponds to R242C in the human TBC1D24 gene).
See, also, the human disease model report 'TBC1D24-related disorders' FBhh0000721.
[updated Oct. 2019 by FlyBase; FBrf0222196]
[DEAFNESS, ONYCHODYSTROPHY, OSTEODYSTROPHY, IMPAIRED INTELLECTUAL DEVELOPMENT, AND SEIZURES SYNDROME; DOORS](https://omim.org/entry/220500)
[TBC1 DOMAIN FAMILY, MEMBER 24; TBC1D24](https://omim.org/entry/613577)
"DOORS" is an abbreviation for the major features of the disorder including deafness; short or absent nails (onychodystrophy); short fingers and toes (osteodystrophy); developmental delay and intellectual disability (previously called mental retardation); and seizures. [Genetics Home Reference, DOORS syndrome; 2018.02.02]
Universal features of this syndrome include profound deafness, usually from infancy, malformations of the nails and digits, and mental retardation. Most patients have coarse facial features with broad nasal bridge, anteverted nares, everted lower lip, and high-arched palate. Ophthalmologic anomalies have been reported in 43% of patients, including optic atrophy and blindness, high myopia, and iris hypoplasia. The disorder follows a progressive course and 32% die in early childhood from seizures or respiratory distress (James et al., 2007; pubmed:17994565). [from MIM:220500; 2018.02.02]
DOORS is caused by homozygous or compound heterozygous mutation in the TBC1D24 gene. [from MIM:220500; 2018.02.02]
TBC1D24 encodes a protein with a conserved domain, referred to as the TBC domain, characteristic of proteins that interact with GTPases. TBC domain proteins may serve as GTPase-activating proteins for Rab small GTPases, which are involved in the regulation of membrane trafficking. [Gene Cards, TBC1D24; 2018.02.02]
The TBC1D24 gene encodes a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins, which coordinate Rab proteins and other GTPases for the proper transport of intracellular vesicles (summary by Campeau et al., 2014; pubmed:24291220). [from MIM:613577; 2018.02.02]
One to one: 1 human to 1 Drosophila
High-scoring ortholog of human TBC1D24 (1 Drosophila to 1 human); Dmel\sky shares 30% identity and 45% similarity with the human gene.
