TBC1D24 – Autosomal dominant nonsyndromic hearing loss

TBC1D24 encodes a protein combining a Tre2/Bub2/Cdc16 (TBC) domain and a TBC/lysin catalytic (TLDc) domain, involved in synaptic vesicle trafficking and oxidative stress resistance. Heterozygous missense variants in TBC1D24 cause DFNA65, an autosomal dominant nonsyndromic hearing loss characterized by progressive, postlingual sensorineural impairment ([PMID:38413761]).

Genetic Evidence

Autosomal dominant inheritance is supported by segregation of a novel heterozygous variant c.1459C>T (p.His487Tyr) with hearing loss in a three-generation family, affecting at least 3 relatives ([PMID:38413761]). Two other dominant variants, c.533C>T (p.Ser178Leu) and c.919A>C (p.Asn307His), have been reported in unrelated families, totaling at least 7 affected individuals across three pedigrees ([PMID:33281559], [PMID:33986365]). All variants are missense substitutions clustering in the TLDc domain or interdomain interface, with no loss-of-function alleles observed in dominant cases.

Functional Evidence

Conservation analysis shows high evolutionary constraint at His487, Ser178, and Asn307. Structural modeling and molecular dynamics simulations indicate that p.His487Tyr alters domain–domain interactions, protein thermodynamic stability, elasticity, RMSD, RMSF, Rg, and SASA consistent with pathogenicity ([PMID:38413761], [PMID:33281559]). These in silico and in vitro data concord with the late-onset progressive phenotype observed in human carriers.

Integration and Clinical Utility

Collectively, genetic and experimental evidence support a moderate clinical validity for TBC1D24 in autosomal dominant nonsyndromic hearing loss. Identification of TBC1D24 variants in affected families enables molecular diagnosis, informs prognosis of progressive hearing decline, and guides genetic counseling. Functional modeling may assist variant interpretation in diagnostic pipelines.

Key Take-home: TBC1D24 missense variants causing interdomain disruption underlie progressive, postlingual DFNA65, supporting targeted genetic testing in dominant nonsyndromic hearing loss.

References

• Scientific reports • 2024 • Investigation of a novel TBC1D24 variation causing autosomal dominant non-syndromic hearing loss. PMID:38413761
• Frontiers in cellular neuroscience • 2020 • A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation. PMID:33281559
• Scientific reports • 2021 • TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss. PMID:33986365

Evidence Based Scoring (AI generated)