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PLoS Genet 2020 Sep 28;169:e1009028. doi: 10.1371/journal.pgen.1009028.
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A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals.

Rivas VN , Magdesian KG , Fagan S , Slovis NM , Luethy D , Javsicas LH , Caserto BG , Miller AD , Dahlgren AR , Peterson J , Hales EN , Peng S , Watson KD , Khokha MK , Finno CJ .

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.

PubMed ID: 32986719
PMC ID: PMC7544121
Article link: PLoS Genet
Grant support: [+]

Genes referenced: calca casr pth rapgef5

Disease Ontology terms: hypoparathyroidism
Phenotypes: Xtr wt + Equs RAPGEF5 mRNA (Fig. 5 B ) [+]

Article Images: [+] show captions
References [+] :
Altschul, Basic local alignment search tool. 1990, Pubmed