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

Marchant, Thomas W; Dietschi, Elisabeth; Rytz, Ulrich; Schawalder, Peter; Jagannathan, Vidya; Hadji Rasouliha, Sheida; Gurtner, Corinne; Waldvogel, Andreas; Harrington, Ronan S; Drögemüller, Michaela; Kidd, Jeffrey; Ostrander, Elaine A; Warr, Amanda; Watson, Mick; Argyle, David; Ter Haar, Gert; Clements, Dylan N; Leeb, Tosso; Schoenebeck, Jeffrey J (2019). An ADAMTS3 missense variant is associated with Norwich Terrier upper airway syndrome. PLoS genetics, 15(5), e1008102. Public Library of Science 10.1371/journal.pgen.1008102

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV)
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > Small Animal Clinic > Small Animal Clinic, Surgery
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > Small Animal Clinic
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Dietschi, Elisabeth; Rytz, Ulrich; Schawalder, Peter; Jagannathan, Vidya; Hadji Rasouliha, Sheida; Gurtner, Corinne; Waldvogel, Andreas; Drögemüller, Michaela and Leeb, Tosso

Subjects:

600 Technology > 630 Agriculture
500 Science > 590 Animals (Zoology)
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1553-7390

Publisher:

Public Library of Science

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

05 Jun 2019 16:13

Last Modified:

23 Oct 2019 08:05

Publisher DOI:

10.1371/journal.pgen.1008102

PubMed ID:

31095560

BORIS DOI:

10.7892/boris.130781

URI:

https://boris.unibe.ch/id/eprint/130781

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