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

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

Author information

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.

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.

PMID:
29309402
PMCID:
PMC5993672
DOI:
10.1038/gim.2017.155
[Indexed for MEDLINE]
Free PMC Article

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