Cargando…
A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs
Laryngeal paralysis (LP) is the inability to abduct the arytenoid cartilages during inspiration, resulting in a partial to complete airway obstruction and consequent respiratory distress. Different forms of LP with varying age of onset exist in dogs. Hereditary early onset forms were reported in sev...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812752/ https://www.ncbi.nlm.nih.gov/pubmed/31647804 http://dx.doi.org/10.1371/journal.pgen.1008416 |
_version_ | 1783462700464996352 |
---|---|
author | Hadji Rasouliha, Sheida Barrientos, Laura Anderegg, Linda Klesty, Carina Lorenz, Jessica Chevallier, Lucie Jagannathan, Vidhya Rösch, Sarah Leeb, Tosso |
author_facet | Hadji Rasouliha, Sheida Barrientos, Laura Anderegg, Linda Klesty, Carina Lorenz, Jessica Chevallier, Lucie Jagannathan, Vidhya Rösch, Sarah Leeb, Tosso |
author_sort | Hadji Rasouliha, Sheida |
collection | PubMed |
description | Laryngeal paralysis (LP) is the inability to abduct the arytenoid cartilages during inspiration, resulting in a partial to complete airway obstruction and consequent respiratory distress. Different forms of LP with varying age of onset exist in dogs. Hereditary early onset forms were reported in several dog breeds. In most breeds, hereditary LP is associated with other neurologic pathologies. Using a genome-wide association study and haplotype analyses, we mapped a major genetic risk factor for an early onset LP in Miniature Bull Terriers to a ~1.3 Mb interval on chromosome 11. Whole genome sequencing of an affected Miniature Bull Terrier and comparison to 598 control genomes revealed a 36 bp insertion into exon 15 of the RAPGEF6 gene (c.1793_1794ins36). The imperfect genotype-phenotype correlation suggested a complex mode of inheritance with a major genetic risk factor involving a recessive risk allele. Homozygosity for the insertion was associated with a 10- to 17-fold increased risk for LP. The insertion allele was only found in Miniature Bull Terriers and Bull Terriers. It was absent from >1000 control dogs of other dog breeds. The insertion sequence contains a splice acceptor motif leading to aberrant splicing in transcripts originating from the mutant allele (r.1732_1780del). This leads to a frameshift and a premature stop codon, p.(Ile587ProfsTer5), removing 64% of the open reading frame. Our results suggest an important role of RAPGEF6 in laryngeal nerve function and provide new clues to its physiological significance. |
format | Online Article Text |
id | pubmed-6812752 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-68127522019-11-03 A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs Hadji Rasouliha, Sheida Barrientos, Laura Anderegg, Linda Klesty, Carina Lorenz, Jessica Chevallier, Lucie Jagannathan, Vidhya Rösch, Sarah Leeb, Tosso PLoS Genet Research Article Laryngeal paralysis (LP) is the inability to abduct the arytenoid cartilages during inspiration, resulting in a partial to complete airway obstruction and consequent respiratory distress. Different forms of LP with varying age of onset exist in dogs. Hereditary early onset forms were reported in several dog breeds. In most breeds, hereditary LP is associated with other neurologic pathologies. Using a genome-wide association study and haplotype analyses, we mapped a major genetic risk factor for an early onset LP in Miniature Bull Terriers to a ~1.3 Mb interval on chromosome 11. Whole genome sequencing of an affected Miniature Bull Terrier and comparison to 598 control genomes revealed a 36 bp insertion into exon 15 of the RAPGEF6 gene (c.1793_1794ins36). The imperfect genotype-phenotype correlation suggested a complex mode of inheritance with a major genetic risk factor involving a recessive risk allele. Homozygosity for the insertion was associated with a 10- to 17-fold increased risk for LP. The insertion allele was only found in Miniature Bull Terriers and Bull Terriers. It was absent from >1000 control dogs of other dog breeds. The insertion sequence contains a splice acceptor motif leading to aberrant splicing in transcripts originating from the mutant allele (r.1732_1780del). This leads to a frameshift and a premature stop codon, p.(Ile587ProfsTer5), removing 64% of the open reading frame. Our results suggest an important role of RAPGEF6 in laryngeal nerve function and provide new clues to its physiological significance. Public Library of Science 2019-10-24 /pmc/articles/PMC6812752/ /pubmed/31647804 http://dx.doi.org/10.1371/journal.pgen.1008416 Text en © 2019 Hadji Rasouliha et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Hadji Rasouliha, Sheida Barrientos, Laura Anderegg, Linda Klesty, Carina Lorenz, Jessica Chevallier, Lucie Jagannathan, Vidhya Rösch, Sarah Leeb, Tosso A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs |
title | A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs |
title_full | A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs |
title_fullStr | A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs |
title_full_unstemmed | A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs |
title_short | A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs |
title_sort | rapgef6 variant constitutes a major risk factor for laryngeal paralysis in dogs |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812752/ https://www.ncbi.nlm.nih.gov/pubmed/31647804 http://dx.doi.org/10.1371/journal.pgen.1008416 |
work_keys_str_mv | AT hadjirasoulihasheida arapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT barrientoslaura arapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT anderegglinda arapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT klestycarina arapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT lorenzjessica arapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT chevallierlucie arapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT jagannathanvidhya arapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT roschsarah arapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT leebtosso arapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT hadjirasoulihasheida rapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT barrientoslaura rapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT anderegglinda rapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT klestycarina rapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT lorenzjessica rapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT chevallierlucie rapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT jagannathanvidhya rapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT roschsarah rapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs AT leebtosso rapgef6variantconstitutesamajorriskfactorforlaryngealparalysisindogs |