TBC1D24 – DOORS syndrome

TBC1D24 encodes a presynaptic TBC domain–containing protein implicated in vesicle trafficking and oxidative stress resistance and is causally linked to DOORS syndrome (deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures) (MONDO:0009079; Gene Symbol). DOORS syndrome is a rare autosomal recessive multisystem disorder characterized by sensorineural deafness, absent or dystrophic nails, bony anomalies, seizures, and moderate to severe intellectual disability.

Clinical validity is classified as Strong, supported by identification of pathogenic TBC1D24 variants in 11 unrelated probands from nine families in a multinational cohort of 26 families, with consistent phenotype–genotype correlation across diverse populations ([PMID:24291220]). Genetic evidence includes compound heterozygous and homozygous variants presenting in an autosomal recessive inheritance pattern, with at least two affected siblings reported in one pedigree confirming familial segregation.

Genetic evidence comprises a broad variant spectrum: 13 distinct loss-of-function alleles (nonsense, frameshift, canonical splice) and multiple missense changes dispersed across the TBC and TLDc domains. Recurrent founder mutations, such as p.Arg242His and p.Glu148Ter, have been observed in consanguineous families, and variants affecting highly conserved residues abrogate mRNA stability ([PMID:24291220]). Representative allele: c.1235G>A (p.Trp412Ter).

Functional studies demonstrate that loss-of-function alleles destabilize TBC1D24 transcripts and reduce protein expression in neuronal cells, and mouse models with Tbc1d24 haploinsufficiency exhibit impaired synaptic vesicle endocytosis, enlarged endosomal compartments, and spontaneous seizures mirroring human DOORS syndrome ([PMID:30335140], [PMID:30602030]). Structural analysis of the TBC domain lipid-binding pocket reveals disrupted phosphoinositide interaction for patient-derived mutations, underlying presynaptic vesicle trafficking defects and seizure susceptibility ([PMID:27669036]).

The existence of DOORS syndrome cases without TBC1D24 mutations and identification of SMARCB1 mutations in phenocopies underscore genetic heterogeneity and the need for differential diagnosis ([PMID:25169651]). No studies have definitively refuted the TBC1D24 association with DOORS syndrome; rather, they highlight additional loci in atypical presentations.

Integration of genetic and functional data confirms TBC1D24 pathogenic variants as a strong cause of DOORS syndrome via loss-of-function mechanisms leading to disrupted vesicle dynamics and neurodevelopmental defects. TBC1D24 genetic testing informs definitive diagnosis, enables carrier detection, and guides anticipatory management for seizures, hearing impairment, and orthopedic complications. Key Take-home: Biallelic TBC1D24 variants cause an autosomal recessive multisystem epilepsy–onychodystrophy syndrome with clear diagnostic and therapeutic implications.

References

• Clinical and molecular characterization of DOORS syndrome associated with TBC1D24 mutations • 2014 • Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder… PMID:24291220
• The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons • 2019 • Mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) gene are associated with a range of inherited neurological disorders… PMID:30335140
• The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy • 2019 • Epilepsy, deafness, onychodystrophy, osteodystrophy and intellectual disability are associated with a spectrum of mutations of human TBC1D24… PMID:30602030
• Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function • 2016 • Mutations in TBC1D24 cause severe epilepsy and DOORS syndrome, but the molecular mechanisms underlying these pathologies are unresolved… PMID:27669036
• DOORS syndrome: phenotype, genotype and comparison with Coffin-Siris syndrome • 2014 • DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, mental Retardation, Seizures) is characterized mainly by sensorineural deafness… PMID:25169651

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