Peer-reviewed veterinary case report
A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals.
- Journal:
- PLoS genetics
- Year:
- 2020
- Authors:
- Rivas, Victor N et al.
- Affiliation:
- Department of Population Health and Reproduction · United States
- Species:
- horse
Plain-English summary
In Thoroughbred foals, a serious condition called idiopathic hypocalcemia can lead to muscle spasms and seizures, and it is usually fatal. Researchers studied two affected foals and found that the condition is linked to a genetic mutation that is passed down in an autosomal recessive manner, meaning both parents must carry the gene for a foal to be affected. They discovered a specific genetic change in the RAPGEF5 gene that seems to cause this problem, and further tests showed that this mutation leads to the gene not working properly. This finding is significant because it is the first time a genetic cause for this condition has been identified in any domestic animal. The treatment and management of this condition remain unclear, but the research highlights a critical genetic factor involved.
Abstract
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.
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Search related cases →Original publication: https://pubmed.ncbi.nlm.nih.gov/32986719/