An ADAMTS3 missense variant is associated with Norwich Terrier upper airway syndrome.

Autor: Marchant TW; The Roslin Institute and Royal (Dick) School for Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom., Dietschi E; Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland., Rytz U; Department of Clinical Veterinary Medicine, Division of Small Animal Surgery, Vetsuisse Faculty, University of Bern, Bern, Switzerland., Schawalder P; Department of Clinical Veterinary Medicine, Division of Small Animal Surgery, Vetsuisse Faculty, University of Bern, Bern, Switzerland., Jagannathan V; Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland., Hadji Rasouliha S; Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland., Gurtner C; Institute for Animal Pathology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland., Waldvogel AS; Institute for Animal Pathology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland., Harrington RS; The Roslin Institute and Royal (Dick) School for Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom., Drögemüller M; Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland., Kidd J; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America., Ostrander EA; Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America., Warr A; The Roslin Institute and Royal (Dick) School for Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom., Watson M; The Roslin Institute and Royal (Dick) School for Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom., Argyle D; The Roslin Institute and Royal (Dick) School for Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom., Ter Haar G; Department of Clinical Sciences and Services, Royal Veterinary College, Hertfordshire, United Kingdom., Clements DN; The Roslin Institute and Royal (Dick) School for Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom., Leeb T; Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland., Schoenebeck JJ; The Roslin Institute and Royal (Dick) School for Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2019 May 16; Vol. 15 (5), pp. e1008102. Date of Electronic Publication: 2019 May 16 (Print Publication: 2019).
DOI: 10.1371/journal.pgen.1008102
Abstrakt: In flat-faced dog breeds, air resistance caused by skull conformation is believed to be a major determinant of Brachycephalic Obstructive Airway Syndrome (BOAS). The clinical presentation of BOAS is heterogeneous, suggesting determinants independent of skull conformation contribute to airway disease. Norwich Terriers, a mesocephalic breed, are predisposed to Upper Airway Syndrome (UAS), a disease whose pathological features overlap with BOAS. Our health screening clinic examined and scored the airways of 401 Norwich terriers by laryngoscopy. Genome-wide association analyses of UAS-related pathologies revealed a genetic association on canine chromosome 13 (rs9043975, p = 7.79x10-16). Whole genome resequencing was used to identify causal variant(s) within a 414 kb critical interval. This approach highlighted an error in the CanFam3.1 dog assembly, which when resolved, led to the discovery of a c.2786G>A missense variant in exon 20 of the positional candidate gene, ADAM metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3). In addition to segregating with UAS amongst Norwich Terriers, the ADAMTS3 c.2786G>A risk allele frequency was enriched among the BOAS-susceptible French and (English) Bulldogs. Previous studies indicate that ADAMTS3 loss of function results in lymphoedema. Our results suggest a new paradigm in the understanding of canine upper airway disease aetiology: airway oedema caused by disruption of ADAMTS3 predisposes dogs to respiratory obstruction. These findings will enhance breeding practices and could refine the prognostics of surgical interventions that are often used to treat airway obstruction.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: TL is an associate editor of PLoS Genetics.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje