A GJA9 frameshift variant is associated with polyneuropathy in Leonberger dogs.

Becker, Doreen; Minor, Katie M; Letko, Anna; Ekenstedt, Kari J; Jagannathan, Vidhya; Leeb, Tosso; Shelton, G Diane; Mickelson, James R; Drögemüller, Cord (2017). A GJA9 frameshift variant is associated with polyneuropathy in Leonberger dogs. BMC Genomics, 18(1), p. 662. BioMed Central 10.1186/s12864-017-4081-z

LPN2 BMC Genomics 2017.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (1MB) | Preview


Many inherited polyneuropathies (PN) observed in dogs have clinical similarities to the genetically heterogeneous group of Charcot-Marie-Tooth (CMT) peripheral neuropathies in humans. The canine disorders collectively show a variable expression of progressive clinical signs and ages of onset, and different breed prevalences. Previously in the Leonberger breed, a variant highly associated with a juvenile-onset PN was identified in the canine orthologue of a CMT-associated gene. As this deletion in ARHGEF10 (termed LPN1) does not explain all cases, PN in this breed may encompass variants in several genes with similar clinical and histopathological features.


A genome-wide comparison of 173 k SNP genotypes of 176 cases, excluding dogs homozygous for the ARHGEF10 variant, and 138 controls, was carried out to detect further PN-associated variants. A single suggestive significant association signal on CFA15 was found. The genome of a PN-affected Leonberger homozygous for the associated haplotype was sequenced and variants in the 7.7 Mb sized critical interval were identified. These variants were filtered against a database of variants observed in 202 genomes of various dog breeds and 3 wolves, and 6 private variants in protein-coding genes, all in complete linkage disequilibrium, plus 92 non-coding variants were revealed. Five of the coding variants were predicted to have low or moderate effect on the encoded protein, whereas a 2 bp deletion in GJA9 results in a frameshift of high impact. GJA9 encodes connexin 59, a connexin gap junction family protein, and belongs to a group of CMT-associated genes that have emerged as important components of peripheral myelinated nerve fibers. The association between the GJA9 variant and PN was confirmed in an independent cohort of 296 cases and 312 controls. Population studies showed a dominant mode of inheritance, an average age of onset of approximately 6 years, and incomplete penetrance.


This GJA9 variant represents a highly probable candidate variant for another form of PN in Leonberger dogs, which we have designated LPN2, and a new candidate gene for CMT disease. To date, approximately every third PN-diagnosed Leonberger dog can be explained by the ARHGEF10 or GJA9 variants, and we assume that additional genetic heterogeneity in this condition exists in the breed.

Item Type:

Journal Article (Original Article)


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

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Becker, Doreen, Letko, Anna, Jagannathan, Vidya, Leeb, Tosso, Drögemüller, Cord


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




BioMed Central




Cord Drögemüller

Date Deposited:

06 Nov 2017 15:43

Last Modified:

05 Dec 2022 15:07

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Charcot-Marie-tooth Connexin genes Connexons Dog Gap junctions Gene test Genome wide association Neurological disorder Peripheral nerve Polyneuropathy Rare disease Whole-genome resequencing





Actions (login required)

Edit item Edit item
Provide Feedback