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

Letko, Anna; Minor, Katie M; Friedenberg, Steven G; Shelton, G Diane; Salvador, Jill Pesayco; Mandigers, Paul J J; Leegwater, Peter A J; Winkler, Paige A; Petersen-Jones, Simon M; Stanley, Bryden J; Ekenstedt, Kari J; Johnson, Gary S; Hansen, Liz; Jagannathan, Vidya; Mickelson, James R; Drögemüller, Cord (2020). A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy. Genes, 11(12) MDPI, Molecular Diversity Preservation International 10.3390/genes11121426

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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.

Item Type:

Journal Article (Original Article)


05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Letko, Anna, Jagannathan, Vidya, Drögemüller, Cord


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




MDPI, Molecular Diversity Preservation International




Cord Drögemüller

Date Deposited:

03 Dec 2020 10:20

Last Modified:

05 Dec 2022 15:42

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Canis familiaris Labrador retriever Leonberger Saint Bernard contactin neurological disorder rare disease whole-genome sequencing





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