A C-terminal nonsense mutation links PTPRQ with autosomal-dominant hearing loss, DFNA73

Genet Med. 2018 Jun;20(6):614-621. doi: 10.1038/gim.2017.155. Epub 2017 Oct 12.


PurposeHearing loss is genetically extremely heterogeneous, making it suitable for next-generation sequencing (NGS). We identified a four-generation family with nonsyndromic mild to severe hearing loss of the mid- to high frequencies and onset from early childhood to second decade in seven members.MethodsNGS of 66 deafness genes, Sanger sequencing, genome-wide linkage analysis, whole-exome sequencing (WES), semiquantitative reverse-transcriptase polymerase chain reaction.ResultsWe identified a heterozygous nonsense mutation, c.6881G>A (p.Trp2294*), in the last coding exon of PTPRQ. PTPRQ has been linked with recessive (DFNB84A), but not dominant deafness. NGS and Sanger sequencing of all exons (including alternatively spliced 5' and N-scan-predicted exons of a putative "extended" transcript) did not identify a second mutation. The highest logarithm of the odds score was in the PTPRQ-containing region on chromosome 12, and p.Trp2294* cosegregated with hearing loss. WES did not identify other cosegregating candidate variants from the mapped region. PTPRQ expression in patient fibroblasts indicated that the mutant allele escapes nonsense-mediated decay (NMD).ConclusionKnown PTPRQ mutations are recessive and do not affect the C-terminal exon. In contrast to recessive loss-of-function mutations, c.6881G>A transcripts may escape NMD. PTPRQTrp2294* protein would lack only six terminal residues and could exert a dominant-negative effect, a possible explanation for allelic deafness, DFNA73, clinically and genetically distinct from DFNB84A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Codon, Nonsense / genetics
  • Deafness / genetics*
  • Exome / genetics
  • Exome Sequencing
  • Exons / genetics
  • Family
  • Female
  • Genetic Linkage
  • Genome-Wide Association Study
  • Hearing Loss / genetics
  • Humans
  • Male
  • Mutation
  • Pedigree
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / genetics*


  • Codon, Nonsense
  • PTPRQ protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3