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Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86.

Abstract
Inherited deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with nonsyndromic deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or nonsyndromic deafness.
AuthorsAtteeq U Rehman, Regie Lyn P Santos-Cortez, Robert J Morell, Meghan C Drummond, Taku Ito, Kwanghyuk Lee, Asma A Khan, Muhammad Asim R Basra, Naveed Wasif, Muhammad Ayub, Rana A Ali, Syed I Raza, University of Washington Center for Mendelian Genomics, Deborah A Nickerson, Jay Shendure, Michael Bamshad, Saima Riazuddin, Neil Billington, Shaheen N Khan, Penelope L Friedman, Andrew J Griffith, Wasim Ahmad, Sheikh Riazuddin, Suzanne M Leal, Thomas B Friedman
JournalAmerican journal of human genetics (Am J Hum Genet) Vol. 94 Issue 1 Pg. 144-52 (Jan 02 2014) ISSN: 1537-6605 [Electronic] United States
PMID24387994 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Carrier Proteins
  • GTPase-Activating Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • TBC1D24 protein, human
Topics
  • Alleles
  • Amino Acid Sequence
  • Carrier Proteins (genetics)
  • Chromosomes, Human, Pair 16 (genetics)
  • Consanguinity
  • Deafness (genetics)
  • Epilepsy (genetics)
  • Exome
  • Exons
  • Female
  • GTPase-Activating Proteins
  • Genes, Recessive
  • Genetic Loci
  • Genome-Wide Association Study
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Membrane Proteins
  • Molecular Sequence Data
  • Mutation
  • Nerve Tissue Proteins
  • Pakistan
  • Pedigree
  • Phenotype
  • Polymorphism, Single Nucleotide
  • RNA, Messenger (genetics, metabolism)
  • Sequence Analysis, DNA

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