Improvements to the Equine Reproduction Service facilities were funded by the school's Dean's Office, which saw the benefit the new space will offer to students and clients. The adjacent laboratory and clinical spaces offer “benchtop to bedside” clinical translation – a hallmark of the future Veterinary Medical Center and a major advantage of seeking treatment at a teaching hospital.

“We are grateful to Dean Lairmore and his office for providing the funding for this space,” said Dr. Carrie Finno, director of the Center for Equine Health. “This project has been more than a year in the making, starting before the pandemic began. It is a tremendous asset for students and residents training here at the Center, and also provides top-notch facilities for our clients.”

The Equine Reproduction Service provides routine and advanced equine reproductive care, including artificial insemination, ultrasonographic pregnancy diagnosis, fertility evaluation, semen collection and evaluation, transvaginal aspiration of oocytes, and embryo transfer.

“This new space gives our service a more efficient place to teach and practice,” said Dujovne. “The opportunities for students in this new treatment and research area will increase significantly, improving the quality of their education in equine reproduction.”

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The study, led by Drs. Carrie Finno and Gary Magdesian,  which was reported in the journal PLoS Genetics. Genetic testing can now be performed at the UC Davis Veterinary Genetics Laboratory to identify horses with the variant and avoid mating carriers that could produce affected foals.

“For Thoroughbred owners and breeders, the loss of a foal has tremendous economic and emotional impacts,” says first author Victor Rivas, who conducted the project as part of his undergraduate training in  Finno's laboratory. “It is important to promote safe and strategic breeding habits by actively breeding horses genetically screened not only for EFIH, but for other diseases that may impact quality of life.”

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 (i.e. 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 hypocalcemia, 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 current 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 analyzed 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 next steps are to assess the allele frequency in a large population of randomly selected Thoroughbreds,” says Finno. “Additionally, we have discussed collaborating with Dr. Nathan Slovis at Hagyard Equine Medical Institute in Kentucky to test for the variant in cases of 'sudden death' in Thoroughbred foals.”

The clinical presentation of EFIH is similar to human familial hypoparathyroidism. Since the RAPGEF5 gene is highly conserved across species, it is a potential new candidate gene for primary hypoparathyroidism in humans.

“This type of research discovery requires a unique collaboration between clinicians, pathologists and basic researchers,” says 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.”

Support for this study was provided by the UC Davis Center for Equine Health.

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