Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss

Clin Genet. 2019 Oct;96(4):300-308. doi: 10.1111/cge.13590. Epub 2019 Jul 10.

Abstract

Hereditary non-syndromic hearing loss is the most common inherited sensory defect in humans. More than 40 genes have been identified as causative genes for autosomal dominant non-syndromic hearing loss (ADNSHL), but there are many other candidate genes that remain to be discovered. We aimed to identify the causative gene mutation for post-lingual progressive ADNSHL in a Chinese family. Whole-exome sequencing, bioinformatic analysis, and Sanger sequencing were used to verify the co-segregation of a novel pathogenic variant (NM_ 001244580, c.511C>T, p.Arg171Cys) in the TRansformation/tRanscription domain-Associated Protein gene associated with hearing loss in a three-generation Chinese family with ADNSHL). Additionally, three more novel variants of transformation/transcription domain associated protein (TRRAP) were detected in 66 sporadic cases of hearing loss. Morpholino oligonucleotides knockdown and clustered regularly interspaced short palindromic repeats/Cas9 knockout zebrafish were constructed to validate the genetic findings. Knockdown or knockout of TRRAP resulted in significant defects in the inner ear of zebrafish, indicating that TRRAP plays an important role in inner ear development. In conclusion, TRRAP (NM_ 001244580, c.511C>T, p.Arg171Cys) co-segregated with hearing loss in a Chinese family with ADNSHL, and TRRAP deficiency caused hearing disability in zebrafish, suggesting TRRAP is a gene associated with ADNSHL.

Keywords: TRRAP; deafness gene; non-syndromic hearing loss; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Female
  • Gene Targeting
  • Genes, Dominant*
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Genotype
  • Hearing Loss / diagnosis*
  • Hearing Loss / genetics*
  • Humans
  • Male
  • Mutation*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Pedigree
  • Phenotype
  • Sequence Analysis, DNA
  • Tomography, X-Ray Computed
  • Whole Exome Sequencing
  • Zebrafish

Substances

  • Adaptor Proteins, Signal Transducing
  • Nuclear Proteins
  • transformation-transcription domain-associated protein