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

English version

Autoři: Victor N. Rivas ^aff001; K. Gary Magdesian ^aff002; Sophia Fagan ^aff003; Nathan M. Slovis ^aff004; Daniela Luethy ^aff005; Laura H. Javsicas ^aff006; Brian G. Caserto ^aff007; Andrew D. Miller ^aff008; Anna R. Dahlgren ^aff001; Janel Peterson ^aff001; Erin N. Hales ^aff001; Sichong Peng ^aff001; Katherine D. Watson ^aff009; Mustafa K. Khokha ^aff003; Carrie J. Finno ^aff001
Působiště autorů: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, United States of America ^aff001; Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, California, United States of America ^aff002; Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America ^aff003; Hagyard Equine Medical Hospital, Lexington, Kentucky, United States of America ^aff004; Department of Clinical Studies–New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America ^aff005; Rhinebeck Equine L.L.P., Rhinebeck, New York, United States of America ^aff006; VetPath Services, Stone Ridge, NY, United States of America ^aff007; Department of Biomedical Sciences, Section of Anatomic Pathology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America ^aff008; Department of Anatomic Pathology, Veterinary Medical Teaching Hospital, University of California-Davis, Davis, California, United States of America ^aff009
Vyšlo v časopise: A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009028
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009028

Souhrn

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 (P_allelic = 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.

Klíčová slova:

Alleles – Animal husbandry – Blood – Equines – Homozygosity – Horses – Xenopus – Parathyroid

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