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News Article

Genetic variant for hypoparathyroidism identified in horses

Genetic testing can now be performed to identify horses with the variant and avoid mating carriers that could produce affected foals

Researchers have identified a genetic cause for the fatal condition equine familial isolated hypoparathyroidism (EFIH) in Thoroughbreds. The study, led by Carrie Finno and Gary Magdesian, at the University of California, Davis School of Veterinary Medicine, is published in PLoS Genetics.

Foals affected with EFIH suffer from low blood calcium concentrations, resulting in involuntary muscle contractions, muscle stiffness that leads to a stiff gait and can progress to an inability to stand, seizures, fevers, and an abnormally fast pulse. Parathyroid hormone is typically produced to increase calcium levels in the body, but in these foals, concentrations are low or “inappropriately” normal (they should be high due to the low calcium). Affected foals die or are euthanized due to poor prognosis. Necropsy results reveal underdeveloped or absent parathyroid glands.

Previously termed idiopathic hypocalcaemia, EFIH has been observed in Thoroughbred foals up to 35 days of age. Disease onset and progression are likely determined by the amount of calcium in the diet early in life. This can vary based on dam milk calcium concentration and the amount of milk ingested.

The study determined an autosomal recessive mode of inheritance and performed whole genome sequencing of two affected foals. A mutation in the rap guanine nucleotide exchange factor 5 (RAPGEF5) gene was present in two copies (homozygous) in both foals. The variant was further analysed in a frog developmental model and demonstrated loss-of-function of the RAPGEF5 protein leading to aberrant development. Based on this data, the researchers hypothesize that RAPGEF5 may play a role in the derivation of the parathyroid gland during development.

The variant was not identified in individuals from 12 other breeds. The allele frequency for the RAPGEF5 variant in an expanded set of 82 randomly selected, unaffected Thoroughbreds was 0.018. An unbiased allele frequency study has not been performed, so the allele frequency in the larger Thoroughbred population is currently unknown.

The researchers now plan to assess the allele frequency in a large population of randomly selected Thoroughbreds.

“This type of research discovery requires a unique collaboration between clinicians, pathologists and basic researchers,” said Finno. “We were incredibly fortunate to have samples submitted from Drs. Slovis, Daniella Leuthy (University of Pennsylvania) and Laura Javsicas (Rhinebeck Equine) and the expertise of Drs. Brian Caserto (VetPath services) and Andrew Miller (Cornell University). Additionally, the ’proof’ of functional results of this genetic mutation would not have been possible without our collaborator from Yale University, Dr. Mustafa Khohka.”

Article: Rivas, V. N., Magdesian, K. G., Fagan, S., Slovis, N. M., Luethy, D., Javsicas, L. H., Caserto, B. G., Miller, A. D., Dahlgren, A. R., Peterson, J., Hales, E. N., Peng, S., Watson, K. D., Khokha, M. K., Finno, C. J. (2020). A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals. PLoS Genetics, 16(9): e1009028, doi: 10.1371/journal.pgen.1009028

Article details

  • Date
  • 23 October 2020
  • Source
  • UC Davis Center for Equine Health
  • Subject(s)
  • Horses and other Equines