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.
Tobias Eisenberger  1 ,  Nataliya Di Donato  2 ,  Christian Decker  1 ,  Andrea Delle Vedove  3 ,  Christine Neuhaus  1 ,  Gudrun Nürnberg  4 ,  Mohammad Toliat  4 ,  Peter Nürnberg  4  5 ,  Dirk Mürbe  6 ,  Hanno Jörn Bolz  1  3
Affiliations
  • 1. Bioscientia Center for Human Genetics, Ingelheim, Germany.
  • 2. Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • 3. Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
  • 4. Cologne Center for Genomics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • 5. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • 6. Division of Phoniatrics and Audiology, Department of Otorhinolaryngology, Technische Universität Dresden, Dresden, Germany.
PMID: 29309402 DOI: 10.1038/gim.2017.155
Abstract

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.