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DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?

Deafness due to mutations in the DFNA5 gene is caused by the aberrant splicing of exon 8, which results in a constitutively active truncated protein. In a large family of European descent (MORL-ADF1) segregating autosomal dominant nonsyndromic hearing loss, we used the OtoSCOPE platform to identify...

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Autores principales: Booth, Kevin T., Azaiez, Hela, Smith, Richard J. H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312536/
https://www.ncbi.nlm.nih.gov/pubmed/32486382
http://dx.doi.org/10.3390/ijms21113951
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author Booth, Kevin T.
Azaiez, Hela
Smith, Richard J. H.
author_facet Booth, Kevin T.
Azaiez, Hela
Smith, Richard J. H.
author_sort Booth, Kevin T.
collection PubMed
description Deafness due to mutations in the DFNA5 gene is caused by the aberrant splicing of exon 8, which results in a constitutively active truncated protein. In a large family of European descent (MORL-ADF1) segregating autosomal dominant nonsyndromic hearing loss, we used the OtoSCOPE platform to identify the genetic cause of deafness. After variant filtering and prioritization, the only remaining variant that segregated with the hearing loss in the family was the previously described c.991-15_991-13delTTC mutation in DFNA5. This 3-base pair deletion in the polypyrimidine of intron 7 is a founder mutation in the East Asian population. Using ethnicity-informative markers and haplotype reconstruction within the DFNA5 gene, we confirmed family MORL-ADF1 is of European ancestry, and that the c.991-15_991-13delTTC mutation arose on a unique haplotype, as compared to that of East Asian families segregating this mutation. In-depth audiometric analysis showed no statistical difference between the audiometric profile of family MORL-ADF1 and the East Asian families. Our data suggest the polypyrimidine tract in intron 7 may be a hotspot for mutations.
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spelling pubmed-73125362020-06-29 DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot? Booth, Kevin T. Azaiez, Hela Smith, Richard J. H. Int J Mol Sci Article Deafness due to mutations in the DFNA5 gene is caused by the aberrant splicing of exon 8, which results in a constitutively active truncated protein. In a large family of European descent (MORL-ADF1) segregating autosomal dominant nonsyndromic hearing loss, we used the OtoSCOPE platform to identify the genetic cause of deafness. After variant filtering and prioritization, the only remaining variant that segregated with the hearing loss in the family was the previously described c.991-15_991-13delTTC mutation in DFNA5. This 3-base pair deletion in the polypyrimidine of intron 7 is a founder mutation in the East Asian population. Using ethnicity-informative markers and haplotype reconstruction within the DFNA5 gene, we confirmed family MORL-ADF1 is of European ancestry, and that the c.991-15_991-13delTTC mutation arose on a unique haplotype, as compared to that of East Asian families segregating this mutation. In-depth audiometric analysis showed no statistical difference between the audiometric profile of family MORL-ADF1 and the East Asian families. Our data suggest the polypyrimidine tract in intron 7 may be a hotspot for mutations. MDPI 2020-05-31 /pmc/articles/PMC7312536/ /pubmed/32486382 http://dx.doi.org/10.3390/ijms21113951 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Booth, Kevin T.
Azaiez, Hela
Smith, Richard J. H.
DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?
title DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?
title_full DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?
title_fullStr DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?
title_full_unstemmed DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?
title_short DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?
title_sort dfna5 (gsdme) c.991-15_991-13delttc: founder mutation or mutational hotspot?
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312536/
https://www.ncbi.nlm.nih.gov/pubmed/32486382
http://dx.doi.org/10.3390/ijms21113951
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