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Article

A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy

1
Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
2
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA
3
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA
4
Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093-0709, USA
5
Department of Clinical Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands
6
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
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Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA
8
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
James R. Mickelson and Cord Drögemüller shared last author.
Genes 2020, 11(12), 1426; https://doi.org/10.3390/genes11121426
Received: 28 October 2020 / Revised: 25 November 2020 / Accepted: 26 November 2020 / Published: 27 November 2020
(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)
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. View Full-Text
Keywords: Canis familiaris; whole-genome sequencing; rare disease; contactin; neurological disorder; Leonberger; Saint Bernard; Labrador retriever Canis familiaris; whole-genome sequencing; rare disease; contactin; neurological disorder; Leonberger; Saint Bernard; Labrador retriever
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MDPI and ACS Style

Letko, A.; Minor, K.M.; Friedenberg, S.G.; Shelton, G.D.; Salvador, J.P.; Mandigers, P.J.J.; Leegwater, P.A.J.; Winkler, P.A.; Petersen-Jones, S.M.; Stanley, B.J.; Ekenstedt, K.J.; Johnson, G.S.; Hansen, L.; Jagannathan, V.; Mickelson, J.R.; Drögemüller, C. A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy. Genes 2020, 11, 1426. https://doi.org/10.3390/genes11121426

AMA Style

Letko A, Minor KM, Friedenberg SG, Shelton GD, Salvador JP, Mandigers PJJ, Leegwater PAJ, Winkler PA, Petersen-Jones SM, Stanley BJ, Ekenstedt KJ, Johnson GS, Hansen L, Jagannathan V, Mickelson JR, Drögemüller C. A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy. Genes. 2020; 11(12):1426. https://doi.org/10.3390/genes11121426

Chicago/Turabian Style

Letko, Anna, Katie M. Minor, Steven G. Friedenberg, G. D. Shelton, Jill P. 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, and Cord Drögemüller. 2020. "A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy" Genes 11, no. 12: 1426. https://doi.org/10.3390/genes11121426

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