Universität zu Köln

Eisenberger, Tobias, Di Donato, Nataliya ORCID: 0000-0001-9439-4677, Decker, Christian, Delle Vedove, Andrea, Neuhaus, Christine, Nuernberg, Gudrun, Toliat, Mohammad, Nuernberg, Peter, Muerbe, Dirk and Bolz, Hanno Joern (2018). A C-terminal nonsense mutation links PTPRQ with autosomal-dominant hearing loss, DFNA73. Genet. Med., 20 (6). S. 614 - 622. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1530-0366

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Abstract

Purpose: Hearing 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. Methods: NGS of 66 deafness genes, Sanger sequencing, genome-wide linkage analysis, whole-exome sequencing (WES), semiquantitative reverse-transcriptase polymerase chain reaction. Results: We 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). Conclusion: Known 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. PTPRQ(Trp2294*) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Eisenberger, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Di Donato, Nataliya UNSPECIFIED orcid.org/0000-0001-9439-4677 UNSPECIFIED Decker, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Delle Vedove, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Neuhaus, Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Toliat, Mohammad UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Muerbe, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolz, Hanno Joern UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-185122
DOI:	10.1038/gim.2017.155
Journal or Publication Title:	Genet. Med.
Volume:	20
Number:	6
Page Range:	S. 614 - 622
Date:	2018
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	NEW YORK
ISSN:	1530-0366
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INOSITOL LIPID PHOSPHATASE; MESSENGER-RNA; SEQUENCE; GENE; TOOL; DISEASE; PROTEIN; IDENTIFICATION; PREDICTION; PROGRAM Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18512