A GJA9 frameshift variant is associated with polyneuropathy in Leonberger dogs

Doreen Becker, Katie M. Minor, Anna Letko, Kari J. Ekenstedt, Vidhya Jagannathan, Tosso Leeb, G. Diane Shelton, James R. Mickelson, Cord Drögemüller

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background: 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. Results: A genome-wide comparison of 173k 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 7.7Mb 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 2bp 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 6years, and incomplete penetrance. Conclusions: 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.

Original languageEnglish (US)
Article number662
JournalBMC Genomics
Volume18
Issue number1
DOIs
StatePublished - Aug 25 2017

Bibliographical note

Funding Information:
The authors gratefully acknowledge Paul Mandigers and Kaspar Matiasek for additional Leonberger samples, and all Leonberger breeders and the Health Committee of the International Union for Leonberger Dogs for their tremendous support during the entire project. The authors wish to thank Brigitta Colomb, Nathalie Besuchet-Schmutz, Muriel Fragnière, Monica Burgers, and Jill Pesayco for their invaluable technical assistance. The Next Generation Sequencing Platform of the University of Bern is acknowledged for performing the whole genome re-sequencing experiment and the Interfaculty Bioinformatics Unit of the University of Bern for providing computational infrastructure. We thank the Dog Biomedical Variant Database Consortium (Gus Aguirre, Catherine André, Danika Bannasch, Oliver Forman, Steve Friedenberg, Eva Furrow, Urs Giger, Christophe Hitte, Marjo Hytönen, Hannes Lohi, Cathryn Mellersh, Anita Oberbauer, Jeffrey Schoenebeck, Sheila Schmutz, Kim Summers, Frank van Steenbeck, Claire Wade) for sharing whole genome sequencing data from control dogs. We also acknowledge all canine researchers who deposited dog whole genome sequencing data into public databases.

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

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