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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, Victor N; Magdesian, K Gary; Fagan, Sophia; Slovis, Nathan M; Luethy, Daniela; Javsicas, Laura H; Caserto, Brian G; Miller, Andrew D; Dahlgren, Anna R; Peterson, Janel; Hales, Erin N; Peng, Sichong; Watson, Katherine D; Khokha, Mustafa K; Finno, Carrie J.
Afiliação
  • Rivas VN; Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, United States of America.
  • Magdesian KG; Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, California, United States of America.
  • Fagan S; Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.
  • Slovis NM; Hagyard Equine Medical Hospital, Lexington, Kentucky, United States of America.
  • Luethy D; Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
  • Javsicas LH; Rhinebeck Equine L.L.P., Rhinebeck, New York, United States of America.
  • Caserto BG; VetPath Services, Stone Ridge, NY, United States of America.
  • Miller AD; Department of Biomedical Sciences, Section of Anatomic Pathology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
  • Dahlgren AR; Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, United States of America.
  • Peterson J; Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, United States of America.
  • Hales EN; Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, United States of America.
  • Peng S; Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, United States of America.
  • Watson KD; Department of Anatomic Pathology, Veterinary Medical Teaching Hospital, University of California-Davis, Davis, California, United States of America.
  • Khokha MK; Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.
  • Finno CJ; Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, United States of America.
PLoS Genet ; 16(9): e1009028, 2020 09.
Article em En | MEDLINE | ID: mdl-32986719
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Códon sem Sentido / Fatores ras de Troca de Nucleotídeo Guanina / Doenças dos Cavalos / Hipocalcemia / Hipoparatireoidismo Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Códon sem Sentido / Fatores ras de Troca de Nucleotídeo Guanina / Doenças dos Cavalos / Hipocalcemia / Hipoparatireoidismo Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article