4.6 Article

Validation of a Chromosome 14 Risk Haplotype for Idiopathic Epilepsy in the Belgian Shepherd Dog Found to Be Associated with an Insertion in the RAPGEF5 Gene

Journal

GENES
Volume 13, Issue 7, Pages -

Publisher

MDPI
DOI: 10.3390/genes13071124

Keywords

dog; idiopathic epilepsy; RAPGEF5; risk haplotype

Funding

  1. Morris Animal Foundation [D05CA-072, DO2CA-62]
  2. American Kennel Club Canine Health Foundation [1613, 02936, 2015, 2614]
  3. Jane and Aatos Erkko Foundation
  4. Academy of Finland
  5. Dog Health Research Fund
  6. Helsinki Institute of Life Science
  7. Wisdom Health
  8. Dutch Belgian Shepherd Breeding association NVBH
  9. Dutch Belgian Shepherd Breeding association BHCN

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A risk haplotype on CFA14 was found to interact with a common risk haplotype on CFA37 in Belgian shepherds, increasing the risk of idiopathic epilepsy. The ACTG haplotype on CFA14 and GG haplotype on CFA37 were associated with elevated risk, and a disruptive insertion in the RAPGEF5 gene adjacent to CFA14 haplotype was identified.
An idiopathic epilepsy (IE) risk haplotype on canine chromosome (CFA) 14 has been reported to interact with the CFA37 common risk haplotype in the Belgian shepherd (BS). Additional IE cases and control dogs were genotyped for the risk haplotypes to validate these previous findings. In the new cohort, the interaction between the two regions significantly elevated IE risk. When the haplotypes were analyzed individually, particular haplotypes on both CFA14 (ACTG) and 37 (GG) were associated with elevated IE risk, though only the CFA37 AA was significantly associated (p < 0.003) with reduced risk in the new cohort. However, the CFA14 ACTG risk was statistically significant when the new and previous cohort data were combined. The frequency of the ACTG haplotype was four-fold higher in BS dogs than in other breeds. Whole genome sequence analysis revealed that a 3-base pair predicted disruptive insertion in the RAPGEF5 gene, which is adjacent to the CFA14 risk haplotype. RAPGEF5 is involved in the Wnt-beta-catenin signaling pathway that is crucial for normal brain function. Although this risk variant does not fully predict the likelihood of a BS developing IE, the association with a variant in a candidate gene may provide insight into the genetic control of canine IE.

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