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

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: 10.1371/journal.pgen.1009028


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.

Klíčová slova:

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


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