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

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.

Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus

“…All samples were genotyped by using either the Axiom Canine Set A or HD arrays (Thermo Fisher Scientific, Waltham, MA, USA) or the Illumina CanineHD BeadChip array (Illumina, San Diego, CA, USA). Samples genotyped on lower density arrays were imputed with Beagle 4.1 [ 21 ] to 500 k density level as described previously [ 22 ]. Quality control filtering steps of the genotyping data were carried out with PLINK v1.9 [ 23 ].…”

Genome Wide Association Study with Imputed Whole Genome Sequence Data Identifies a 431 kb Risk Haplotype on CFA18 for Congenital Laryngeal Paralysis in Alaskan Sled Dogs

“…Congenital Laryngeal paralysis is an inherited condition in dogs in which one or both recurrent laryngeal nerves are impaired, typically by a degenerative process [ 6 , 7 , 8 , 9 ]. This results in the loss of proper functioning of the larynx causing insufficient abduction of the arytenoid cartilages during inspiration resulting in upper airway obstruction [ 10 , 11 ], resulting in breathing difficulties, exercise and heat intolerance, and increased risk of aspiration pneumonia [ 12 ]. Respiratory distress, voice impairment (dysphonia), and inspiratory stridor are the main clinical signs of CLP in dogs [ 5 , 13 ].…”

“…Laryngeal paralysis has been reported in several dog breeds, including Alaskan malamutes [ 18 ], Bull terriers [ 19 ], Bouviers des Flandres [ 9 , 20 ], Siberian huskies [ 21 ], Siberian husky x Alaskan malamute crossbreds [ 7 ], Leonbergers [ 22 ], Dalmatians [ 23 ], Labrador retrievers [ 12 ], Great Pyrenees [ 24 ], and Rottweilers [ 25 , 26 ]. In many of these dogs, laryngeal paralysis is associated with juvenile-onset polyneuropathy, including esophageal dysfunction [ 13 , 22 , 24 , 25 , 26 ].…”

“…In many of these dogs, laryngeal paralysis is associated with juvenile-onset polyneuropathy, including esophageal dysfunction [ 13 , 22 , 24 , 25 , 26 ]. The combination of laryngeal paralysis and polyneuropathy, also known as laryngeal paralysis and polyneuropathy complex (LPPC), has variable ages of onset [ 12 ]. Late-onset forms of LPPC are referred to as geriatric onset laryngeal paralysis polyneuropathy (GOLPP) [ 27 ].…”

“…Late-onset forms of LPPC are referred to as geriatric onset laryngeal paralysis polyneuropathy (GOLPP) [ 27 ]. Though mutations in genes such as RAPGEF6 [ 13 ], GJA9 [ 28 ], ARHGEF10 [ 29 ], CNTNAP1 [ 12 ], RAB3GAP1 [ 30 ], and NDRG1 [ 31 ] have been found to be associated with canine laryngeal paralysis, they were identified in dogs suffering from polyneuropathy. However, CLP in the Alaskan sled dogs in our study was found to be due to mononeuropathy of the recurrent laryngeal nerves without polyneuropathy [ 5 ].…”