A cntnap1 missense variant is associated with canine laryngeal paralysis and polyneuropathy

Anna Letko, Katie M. Minor, Steven G. Friedenberg, G. Diane Shelton, Jill Pesayco Salvador, Paul J.J. Mandigers, Peter A.J. Leegwater, Paige A. Winkler, Simon M. Petersen-Jones, Bryden J. Stanley, Kari J. Ekenstedt, Gary S. Johnson, Liz Hansen, Vidhya Jagannathan, James R. Mickelson, Cord Drögemüller

Research output: Contribution to journalArticlepeer-review

Abstract

Laryngeal paralysis associated with a generalized polyneuropathy (LPPN) most commonly exists in geriatric dogs from a variety of large and giant breeds. The purpose of this study was to discover the underlying genetic and molecular mechanisms in a younger-onset form of this neurodegenerative disease seen in two closely related giant dog breeds, the Leonberger and Saint Bernard. Neuropathology of an affected dog from each breed showed variable nerve fiber loss and scattered inappropriately thin myelinated fibers. Using across-breed genome-wide association, haplotype analysis, and whole-genome sequencing, we identified a missense variant in the CNTNAP1 gene (c.2810G>A; p.Gly937Glu) in which homozygotes in both studied breeds are affected. CNTNAP1 encodes a contactin-associated protein important for organization of myelinated axons. The herein described likely pathogenic CNTNAP1 variant occurs in unrelated breeds at variable frequencies. Individual homozygous mutant LPPN-affected Labrador retrievers that were on average four years younger than dogs affected by geriatric onset laryngeal paralysis polyneuropathy could be explained by this variant. Pathologic changes in a Labrador retriever nerve biopsy from a homozygous mutant dog were similar to those of the Leonberger and Saint Bernard. The impact of this variant on health in English bulldogs and Irish terriers, two breeds with higher CNTNAP1 variant allele frequencies, remains unclear. Pathogenic variants in CNTNAP1 have previously been reported in human patients with lethal congenital contracture syndrome and hypomyelinating neuropathy, including vocal cord palsy and severe respiratory distress. This is the first report of contactin-associated LPPN in dogs characterized by a deleterious variant that most likely predates modern breed establishment.

Original languageEnglish (US)
Article number1426
Pages (from-to)1-14
Number of pages14
JournalGenes
Volume11
Issue number12
DOIs
StatePublished - Dec 2020

Bibliographical note

Funding Information:
The University of Minnesota received a gift from the Leonberger Health Foundation to support research in this breed. Kari J. Ekenstedt (K.J.E.) was supported by the Office of the Director, National Institutes of Health (NIH), under award number K01-OD027051. Other authors have no external funding to report.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Canis familiaris
  • Contactin
  • Labrador retriever
  • Leonberger
  • Neurological disorder
  • Rare disease
  • Saint Bernard
  • Whole-genome sequencing

PubMed: MeSH publication types

  • Journal Article

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