Forskning
Udskriv Udskriv
Switch language
Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults

    Publikation: Bidrag til tidsskriftKommentar/debatForskningpeer review

  4. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  5. Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Oral therapy for riboflavin transporter deficiency - What is the regimen of choice?

    Publikation: Bidrag til tidsskriftLetterForskningpeer review

  2. The Natural History of Hearing Loss in Pendred Syndrome and Non-Syndromic Enlarged Vestibular Aqueduct

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Cochlear implantation in a 10-year old boy with Pendred syndrome and extremely enlarged endolymphatic sacs

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Recurrent, Activating Variants in the Receptor Tyrosine Kinase DDR2 Cause Warburg-Cinotti Syndrome

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  5. Adaptive Processes in Hearing

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Mette Nyegaard
  • Nanna Dahl Rendtorff
  • Morten S Nielsen
  • Thomas J Corydon
  • Ditte Demontis
  • Anna Starnawska
  • Anne Hedemand
  • Annalisa Buniello
  • Francesco Niola
  • Michael Toft Overgaard
  • Suzanne M Leal
  • Wasim Ahmad
  • Friedrik Wikman
  • Kirsten Petersen
  • Dorthe G Crüger
  • Jaap Oostrik
  • Hannie Kremer
  • Niels Tommerup
  • Morten Frödin
  • Karen P Steel
  • Lisbeth Tranebjærg
  • Anders D Børglum
Vis graf over relationer

Nonsyndromic hearing impairment (NSHI) is a highly heterogeneous condition with more than eighty known causative genes. However, in the clinical setting, a large number of NSHI families have unexplained etiology, suggesting that there are many more genes to be identified. In this study we used SNP-based linkage analysis and follow up microsatellite markers to identify a novel locus (DFNA66) on chromosome 6q15-21 (LOD 5.1) in a large Danish family with dominantly inherited NSHI. By locus specific capture and next-generation sequencing, we identified a c.574C>T heterozygous nonsense mutation (p.R192*) in CD164. This gene encodes a 197 amino acid transmembrane sialomucin (known as endolyn, MUC-24 or CD164), which is widely expressed and involved in cell adhesion and migration. The mutation segregated with the phenotype and was absent in 1200 Danish control individuals and in databases with whole-genome and exome sequence data. The predicted effect of the mutation was a truncation of the last six C-terminal residues of the cytoplasmic tail of CD164, including a highly conserved canonical sorting motif (YXXФ). In whole blood from an affected individual, we found by RT-PCR both the wild-type and the mutated transcript suggesting that the mutant transcript escapes nonsense mediated decay. Functional studies in HEK cells demonstrated that the truncated protein was almost completely retained on the plasma cell membrane in contrast to the wild-type protein, which targeted primarily to the endo-lysosomal compartments, implicating failed endocytosis as a possible disease mechanism. In the mouse ear, we found CD164 expressed in the inner and outer hair cells of the organ of Corti, as well as in other locations in the cochlear duct. In conclusion, we have identified a new DFNA locus located on chromosome 6q15-21 and implicated CD164 as a novel gene for hearing impairment.

OriginalsprogEngelsk
TidsskriftP L o S Genetics
Vol/bind11
Udgave nummer7
Sider (fra-til)e1005386
ISSN1553-7390
DOI
StatusUdgivet - jul. 2015

ID: 45848572