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

Zdroje

1. American Horse Council Foundation. Economic Impact of the U.S. Horse Industry. 2017, https://www.horsecouncil.org/product/2017-economic-impact-study-u-s-horse-industry/

2. The Jockey Club. 2020 Fact Book 2020. http://www.jockeyclub.com/Default.asp?section=Resources&area=113.

3. Beyer MJ, Freestone JF, Reimer JM, Bernard WV, Rueve ER. Idiopathic hypocalcemia in foals. J Vet Intern Med. 1997;11(6):356–60. doi: 10.1111/j.1939-1676.1997.tb00480.x 9470161

4. Roszko KL, Bi RD, Mannstadt M. Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2. Front Physiol. 2016;7 : 458. doi: 10.3389/fphys.2016.00458 27803672

5. Gunther T, Chen ZF, Kim J, Priemel M, Rueger JM, Amling M, et al. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature. 2000;406(6792):199–203. doi: 10.1038/35018111 10910362

6. Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, et al. Mutations affecting G-protein subunit alpha11 in hypercalcemia and hypocalcemia. N Engl J Med. 2013;368(26):2476–86. doi: 10.1056/NEJMoa1300253 23802516

7. Lainez S, Schlingmann KP, van der Wijst J, Dworniczak B, van Zeeland F, Konrad M, et al. New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia. Eur J Hum Genet. 2014;22(4):497–504. doi: 10.1038/ejhg.2013.178 23942199

8. Garbe JR, Da Y. Pedigraph: A software tool for the graphing and analysis of large complex pedigrees. Version 2.4 ed. University of Minnesota: Department of Animal Science; 2008.

9. Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 2012;6(2):80–92.

10. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215(3):403–10. doi: 10.1016/S0022-2836(05)80360-2 2231712

11. Burns EN, Bordbari MH, Mienaltowski MJ, Affolter VK, Barro MV, Gianino F, et al. Generation of an equine biobank to be used for Functional Annotation of Animal Genomes project. Anim Genet. 2018;49(6):564–70. doi: 10.1111/age.12717 30311254

12. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The Protein Data Bank. Nucleic Acids Res. 2000;28(1):235–42. doi: 10.1093/nar/28.1.235 10592235

13. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2015;43(Database issue):D512–20. doi: 10.1093/nar/gku1267 25514926

14. Griffin JN, Del Viso F, Duncan AR, Robson A, Hwang W, Kulkarni S, et al. RAPGEF5 Regulates Nuclear Translocation of beta-Catenin. Dev Cell. 2018;44(2):248–60 e4.

15. Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature. 1998;391(6665):357–62. doi: 10.1038/34848 9450748

16. Tian Y, Xu Y, Fu Q, He M. Parathyroid hormone regulates osteoblast differentiation in a Wnt/beta-catenin-dependent manner. Mol Cell Biochem. 2011;355(1–2):211–6. doi: 10.1007/s11010-011-0856-8 21533763

17. Romero G, Sneddon WB, Yang Y, Wheeler D, Blair HC, Friedman PA. Parathyroid hormone receptor directly interacts with dishevelled to regulate beta-Catenin signaling and osteoclastogenesis. J Biol Chem. 2010;285(19):14756–63. doi: 10.1074/jbc.M110.102970 20212039

18. MacLeod RJ. Extracellular calcium-sensing receptor/PTH knockout mice colons have increased Wnt/beta-catenin signaling, reduced non-canonical Wnt signaling, and increased susceptibility to azoxymethane-induced aberrant crypt foci. Lab Invest. 2013;93(5):520–7. doi: 10.1038/labinvest.2013.51 23545937

19. Sanger Institute Zebrafish Mutation Project mutant data submission [Internet]. ZFIN Direct Data Submission. 2013. Available from: http://zfin.org/.

20. Kalbfleisch TS, Rice ES, DePriest MS Jr., Walenz BP, Hestand MS, Vermeesch JR, et al. Improved reference genome for the domestic horse increases assembly contiguity and composition. Commun Biol. 2018;1 : 197. doi: 10.1038/s42003-018-0199-z 30456315

21. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754–60. doi: 10.1093/bioinformatics/btp324 19451168

22. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25(16):2078–9. doi: 10.1093/bioinformatics/btp352 19505943

23. Garrison E, Marth G. Haplotype-based variant detection from short-read sequencing. arXiv preprint arXiv:12073907 [q-bioGN]. 2012.

24. Cingolani P, Patel VM, Coon M, Nguyen T, Land SJ, Ruden DM, et al. Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift. Front Genet. 2012;3 : 35. doi: 10.3389/fgene.2012.00035 22435069

25. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75. doi: 10.1086/519795 17701901

26. Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29(1):24–6. doi: 10.1038/nbt.1754 21221095

27. Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, et al. Primer3—new capabilities and interfaces. Nucleic Acids Res. 2012;40(15):e115. doi: 10.1093/nar/gks596 22730293

28. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. doi: 10.1093/bioinformatics/bts635 23104886

29. Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C. Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods. 2017;14(4):417–9. doi: 10.1038/nmeth.4197 28263959

30. del Viso F, Khokha M. Generating diploid embryos from Xenopus tropicalis. Methods Mol Biol. 2012;917 : 33–41. doi: 10.1007/978-1-61779-992-1_3 22956081

31. Khokha MK, Chung C, Bustamante EL, Gaw LW, Trott KA, Yeh J, et al. Techniques and probes for the study of Xenopus tropicalis development. Dev Dyn. 2002;225(4):499–510. doi: 10.1002/dvdy.10184 12454926

32. Nieuwkoop PD, Faber J. Normal Table of Xenopus Laevis (Daudin). New York, NY: Routledge; 1994.

Článek Coordinate genomic association of transcription factors controlled by an imported quorum sensing peptide in Cryptococcus neoformans

Článek Using prior information from humans to prioritize genes and gene-associated variants for complex traits in livestock

Článek The STRIPAK signaling complex regulates dephosphorylation of GUL1, an RNA-binding protein that shuttles on endosomes

Článek PIG-1 MELK-dependent phosphorylation of nonmuscle myosin II promotes apoptosis through CES-1 Snail partitioning

Článek Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity

Článek A mega-analysis of expression quantitative trait loci in retinal tissue

Článek Genetic analysis of the modern Australian labradoodle dog breed reveals an excess of the poodle genome

Článek Trichoderma reesei XYR1 activates cellulase gene expression via interaction with the Mediator subunit TrGAL11 to recruit RNA polymerase II

Článek The Arabidopsis PHD-finger protein EDM2 has multiple roles in balancing NLR immune receptor gene expression

Článek A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

Článek Excess crossovers impede faithful meiotic chromosome segregation in C. elegans