Journal Article

A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals

Magdesian, K. Gary, Luethy, Daniela, Fagan, Sophia, Javsicas, Laura H., Slovis, Nathan M., Khokha, Mustafa K., Hales, Erin N., Dahlgren, Anna R., Watson, Katherine D., Rivas, Victor N., Peterson, Janel, Peng, Sichong, Finno, Carrie J., Caserto, Brian G., Miller, Andrew D.

2020

Overview

Idiopathic hypocalcemia in Thoroughbred (TB) foals causes tetany and seizures and is invariably fatal. Based upon the similarity of this disease with human familial hypoparathyroidism and occurrence only in the TB breed, we conducted a genetic investigation on two affected TB foals. Familial hypoparathyroidism was identified, and pedigree analysis suggested an autosomal recessive (AR) mode of inheritance. We performed whole-genome sequencing of the two foals, their unaffected dams and four unaffected, unrelated TB horses. Both homozygosity mapping and an association analysis were used to prioritize potential genetic variants. Of the 2,808 variants that significantly associated with the phenotype using an AR mode of inheritance (P<0.02) and located within a region of homozygosity, 1,507 (54%) were located in a 9.7 Mb region on chr4 (44.9-54.6 Mb). Within this region, a nonsense variant (RAPGEF5 c.2624C>A,p.Ser875*) was significantly associated with the hypoparathyroid phenotype (Pallelic = 0.008). Affected foals were homozygous for the variant, with two additional affected foals subsequently confirmed in 2019. Necropsies of all affected foals failed to identify any histologically normal parathyroid glands. Because the nonsense mutation in RAPGEF5 was near the C-terminal end of the protein, the impact on protein function was unclear. Therefore, we tested the variant in our Xenopus overexpression model and demonstrated RAPGEF5 loss-of-function. This RAPGEF5 variant represents the first genetic variant for hypoparathyroidism identified in any domestic animal species.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adrenal glands / Animals / Association analysis / Biology and Life Sciences / Codon, Nonsense / Diseases / Domestic animals / Edema / Embryo, Nonmammalian / Female / Foals / Funding / Gene mapping / Genes / Genetic aspects / Genetic diversity / Genomes / Genomics / Guanine / Guanine nucleotide exchange factor / Heredity / Homozygote / Horse Diseases - etiology / Horse Diseases - genetics / Horses / Hypocalcemia / Hypocalcemia - genetics / Hypocalcemia - pathology / Hypocalcemia - veterinary / Hypoparathyroidism / Hypoparathyroidism - genetics / Hypoparathyroidism - pathology / Hypoparathyroidism - veterinary / Juveniles / Male / Medicine and Health Sciences / Mutation / Nonsense mutation / Parathyroid / Pathology / Pediatrics / Pedigree / Phenotypes / Population / ras Guanine Nucleotide Exchange Factors - chemistry / ras Guanine Nucleotide Exchange Factors - genetics / ras Guanine Nucleotide Exchange Factors - metabolism / Research and Analysis Methods / Risk factors / Seizures / Supervision / Tetany / Thoroughbred horse / Thymus gland / Thyroid gland / Transcription factors / Veterinary colleges / Veterinary medicine / Whole Genome Sequencing / Xenopus - embryology