Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness

Genes (Basel). 2020 Sep 24;11(10):1122. doi: 10.3390/genes11101122.


Human pathogenic variants of TBC1D24 are associated with clinically heterogeneous phenotypes, including recessive nonsyndromic deafness DFNB86, dominant nonsyndromic deafness DFNA65, seizure accompanied by deafness, a variety of isolated seizure phenotypes and DOORS syndrome, characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability and seizures. Thirty-five pathogenic variants of human TBC1D24 associated with deafness have been reported. However, functions of TBC1D24 in the inner ear and the pathophysiology of TBC1D24-related deafness are unknown. In this study, a novel splice-site variant of TBC1D24 c.965 + 1G > A in compound heterozygosity with c.641G > A p.(Arg214His) was found to be segregating in a Pakistani family. Affected individuals exhibited, either a deafness-seizure syndrome or nonsyndromic deafness. In human temporal bones, TBC1D24 immunolocalized in hair cells and spiral ganglion neurons, whereas in mouse cochlea, Tbc1d24 expression was detected only in spiral ganglion neurons. We engineered mouse models of DFNB86 p.(Asp70Tyr) and DFNA65 p.(Ser178Leu) nonsyndromic deafness and syndromic forms of deafness p.(His336Glnfs*12) that have the same pathogenic variants that were reported for human TBC1D24. Unexpectedly, no auditory dysfunction was detected in Tbc1d24 mutant mice, although homozygosity for some of the variants caused seizures or lethality. We provide some insightful supporting data to explain the phenotypic differences resulting from equivalent pathogenic variants of mouse Tbc1d24 and human TBC1D24.

Keywords: DFNA65; DFNB86; DOORS; Tbc1d24 mouse models; hearing loss; human temporal bone; syndromic deafness.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Child, Preschool
  • Deafness / genetics
  • Deafness / pathology*
  • Disease Models, Animal*
  • Female
  • GTPase-Activating Proteins / chemistry
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism
  • Humans
  • Infant
  • Male
  • Mice
  • Mutation*
  • Spasms, Infantile / genetics
  • Spasms, Infantile / pathology*


  • GTPase-Activating Proteins
  • TBC1D24 protein, human
  • Tbc1d24 protein, mouse

Supplementary concepts

  • Infantile Epileptic-Dyskinetic Encephalopathy
  • Nonsyndromic Deafness