A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals
| Autor: | Anna R. Dahlgren, Laura H. Javsicas, Victor N. Rivas, Mustafa K. Khokha, Nathan M. Slovis, Janel Peterson, K. Gary Magdesian, Katherine D. Watson, Sichong Peng, Carrie J. Finno, Daniela Luethy, Brian G. Caserto, Erin N. Hales, Sophia Fagan, Andrew D. Miller |
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| Přispěvatelé: | Barsh, Gregory S |
| Rok vydání: | 2020 |
| Předmět: |
Male
Cancer Research Embryo Nonmammalian Parathyroid Heredity Physiology animal diseases Xenopus QH426-470 Homozygosity 0302 clinical medicine Medicine and Health Sciences 2.1 Biological and endogenous factors Animal Husbandry Aetiology Genetics (clinical) Animal Management Genetics Mammals 0303 health sciences Nonmammalian Homozygote Eukaryota Agriculture Animal Models Disease gene identification Phenotype Body Fluids Pedigree Blood Experimental Organism Systems Codon Nonsense Embryo Vertebrates Frogs ras Guanine Nucleotide Exchange Factors Female medicine.symptom Anatomy Research Article Tetany Hypoparathyroidism Nonsense mutation Equines Endocrine System Biology Research and Analysis Methods Amphibians 03 medical and health sciences Model Organisms Rare Diseases medicine Animals Horses Allele Codon Molecular Biology Ecology Evolution Behavior and Systematics Alleles 030304 developmental biology Genetic association Hypocalcemia Whole Genome Sequencing Familial isolated hypoparathyroidism Organisms Biology and Life Sciences medicine.disease Nonsense Genetic Loci Amniotes Animal Studies Horse Diseases Zoology 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS genetics, vol 16, iss 9 PLoS Genetics PLoS Genetics, Vol 16, Iss 9, p e1009028 (2020) |
| Popis: | 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 (PA,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. Author summary The Thoroughbred breeding industry in the United States produces a total impact of $6 billion. A lethal hypocalcemic syndrome was first described in young Thoroughbred horses in 1997. Affected foals suffer from seizures due to low blood calcium concentrations in the first few weeks of life. Our clinical evaluation of affected foals supported a diagnosis of primary hypoparathyroidism, and the disease appeared to be inherited as an autosomal recessive trait. Whole-genome sequencing of two affected foals identified a nonsense variant in RAPGEF5. Two additional affected foals were subsequently genotyped and also homozygous for the nonsense variant. Overexpression of the equine variant in frog embryos demonstrated loss-of-function. Genetic testing is now available to screen carrier Thoroughbreds and the disease was renamed equine isolated familial hypoparathyroidism (EIFH). |
| Databáze: | OpenAIRE |
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