A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment.
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-b...
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doaj-c3cde509dda1488686ad20653467c3ea2020-11-25T01:32:48ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042015-07-01117e100538610.1371/journal.pgen.1005386A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment.Mette NyegaardNanna D RendtorffMorten S NielsenThomas J CorydonDitte DemontisAnna StarnawskaAnne HedemandAnnalisa BunielloFrancesco NiolaMichael T OvergaardSuzanne M LealWasim AhmadFriedrik P WikmanKirsten B PetersenDorthe G CrügerJaap OostrikHannie KremerNiels TommerupMorten FrödinKaren P SteelLisbeth TranebjærgAnders D BørglumNonsyndromic 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.http://europepmc.org/articles/PMC4510537?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mette Nyegaard Nanna D Rendtorff Morten S Nielsen Thomas J Corydon Ditte Demontis Anna Starnawska Anne Hedemand Annalisa Buniello Francesco Niola Michael T Overgaard Suzanne M Leal Wasim Ahmad Friedrik P Wikman Kirsten B Petersen Dorthe G Crüger Jaap Oostrik Hannie Kremer Niels Tommerup Morten Frödin Karen P Steel Lisbeth Tranebjærg Anders D Børglum |
spellingShingle |
Mette Nyegaard Nanna D Rendtorff Morten S Nielsen Thomas J Corydon Ditte Demontis Anna Starnawska Anne Hedemand Annalisa Buniello Francesco Niola Michael T Overgaard Suzanne M Leal Wasim Ahmad Friedrik P Wikman Kirsten B Petersen Dorthe G Crüger Jaap Oostrik Hannie Kremer Niels Tommerup Morten Frödin Karen P Steel Lisbeth Tranebjærg Anders D Børglum A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment. PLoS Genetics |
author_facet |
Mette Nyegaard Nanna D Rendtorff Morten S Nielsen Thomas J Corydon Ditte Demontis Anna Starnawska Anne Hedemand Annalisa Buniello Francesco Niola Michael T Overgaard Suzanne M Leal Wasim Ahmad Friedrik P Wikman Kirsten B Petersen Dorthe G Crüger Jaap Oostrik Hannie Kremer Niels Tommerup Morten Frödin Karen P Steel Lisbeth Tranebjærg Anders D Børglum |
author_sort |
Mette Nyegaard |
title |
A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment. |
title_short |
A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment. |
title_full |
A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment. |
title_fullStr |
A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment. |
title_full_unstemmed |
A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment. |
title_sort |
novel locus harbouring a functional cd164 nonsense mutation identified in a large danish family with nonsyndromic hearing impairment. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2015-07-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4510537?pdf=render |
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