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Frameshift Variant Associated with Novel Hoof Specific Phenotype in Connemara Ponies


Inherited diseases affecting only the nails in humans are rare; however, humans do not support themselves entirely on one appendage. Horses bear their entire weight on their third toe, resulting in a large amount of force on each hoof. An inherited disease characterized by a phenotype restricted to separation and breaking of the dorsal hoof wall was identified in a specific breed of pony, the Connemara. This disease has been termed hoof wall separation disease (HWSD). Parents of affected ponies appeared clinically normal, suggesting an autosomal recessive mode of inheritance. A genome-wide association analysis identified a region associated with HWSD which was further assessed through whole genome next-generation sequencing and genotyping of potential variants. Here, we present the discovery of a frameshift variant, leading to a premature stop codon in SERPINB11 of HWSD-affected ponies. Significantly decreased expression of the SERPINB11 transcript was identified in the hoof capsule of HWSD-affected ponies. This study describes the first genetic variant associated with a hoof wall specific phenotype and suggests a role of SERPINB11 in maintaining hoof wall structure.


Vyšlo v časopise: Frameshift Variant Associated with Novel Hoof Specific Phenotype in Connemara Ponies. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005122
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005122

Souhrn

Inherited diseases affecting only the nails in humans are rare; however, humans do not support themselves entirely on one appendage. Horses bear their entire weight on their third toe, resulting in a large amount of force on each hoof. An inherited disease characterized by a phenotype restricted to separation and breaking of the dorsal hoof wall was identified in a specific breed of pony, the Connemara. This disease has been termed hoof wall separation disease (HWSD). Parents of affected ponies appeared clinically normal, suggesting an autosomal recessive mode of inheritance. A genome-wide association analysis identified a region associated with HWSD which was further assessed through whole genome next-generation sequencing and genotyping of potential variants. Here, we present the discovery of a frameshift variant, leading to a premature stop codon in SERPINB11 of HWSD-affected ponies. Significantly decreased expression of the SERPINB11 transcript was identified in the hoof capsule of HWSD-affected ponies. This study describes the first genetic variant associated with a hoof wall specific phenotype and suggests a role of SERPINB11 in maintaining hoof wall structure.


Zdroje

1. Hamrick MW (2001) Development and evolution of the mammalian limb: adaptive diversification of nails, hooves, and claws. Evol Dev 3: 355–363. 11710767

2. Hodson E, Clayton HM, Lanovaz JL (2000) The forelimb in walking horses: 1. Kinematics and ground reaction forces. Equine Vet J 32: 287–294. 10952376

3. Freire-Maia N (1971) Ectodermal dysplasias. Hum Hered 21: 309–312. 5139249

4. Kiuru M, Kurban M, Itoh M, Petukhova L, Shimomura Y, et al. (2011) Hereditary leukonychia, or porcelain nails, resulting from mutations in PLCD1. Am J Hum Genet 88: 839–844. doi: 10.1016/j.ajhg.2011.05.014 21665001

5. Bergmann C, Senderek J, Anhuf D, Thiel CT, Ekici AB, et al. (2006) Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia. Am J Hum Genet 79: 1105–1109. 17186469

6. Sato-Matsumura KC, Yasukawa K, Tomita Y, Shimizu H (2002) Toenail dystrophy with COL7A1 glycine substitution mutations segregates as an autosomal dominant trait in 2 families with dystrophic epidermolysis bullosa. Arch Dermatol 138: 269–271. 11843659

7. Frojmark AS, Schuster J, Sobol M, Entesarian M, Kilander MB, et al. (2011) Mutations in Frizzled 6 cause isolated autosomal-recessive nail dysplasia. Am J Hum Genet 88: 852–860. doi: 10.1016/j.ajhg.2011.05.013 21665003

8. Hamm H, Karl S, Brocker EB (2000) Isolated congenital nail dysplasia: a new autosomal dominant condition. Arch Dermatol 136: 1239–1243. 11030770

9. Askew DJ, Cataltepe S, Kumar V, Edwards C, Pace SM, et al. (2007) SERPINB11 is a new noninhibitory intracellular serpin. Common single nucleotide polymorphisms in the scaffold impair conformational change. J Biol Chem 282: 24948–24960. 17562709

10. Heit C, Jackson BC, McAndrews M, Wright MW, Thompson DC, et al. (2013) Update of the human and mouse SERPIN gene superfamily. Hum Genomics 7: 22. doi: 10.1186/1479-7364-7-22 24172014

11. Cripps PJ, Eustace RA (1999) Radiological measurements from the feet of normal horses with relevance to laminitis. Equine Vet J 31: 427–432. 10505960

12. Karolchik D, Barber GP, Casper J, Clawson H, Cline MS, et al. (2014) The UCSC Genome Browser database: 2014 update. Nucleic Acids Res 42: D764–770. doi: 10.1093/nar/gkt1168 24270787

13. Doan R, Cohen ND, Sawyer J, Ghaffari N, Johnson CD, et al. (2012) Whole-genome sequencing and genetic variant analysis of a Quarter Horse mare. BMC Genomics 13: 78. doi: 10.1186/1471-2164-13-78 22340285

14. British Connemara Pony Society [Internet]. (2008) Breed Standard. Available from: http://www.britishconnemaras.co.uk/index.php?id=208.

15. Priestley GC. An introduction to the skin and its diseases. In: Priestley GC, editors. Molecular Aspects of Dermatology. Chichester: John Wiley & Sons; 1993. p.1–17.

16. Carter RA, Shekk V, de Laat MA, Pollitt CC, Galantino-Homer HL (2010) Novel keratins identified by quantitative proteomic analysis as the major cytoskeletal proteins of equine (Equus caballus) hoof lamellar tissue. J Anim Sci 88: 3843–3855. doi: 10.2527/jas.2010-2964 20622188

17. Reilly JD, Cottress DF, Martin RJ, Cuddeford D (1996) Tubule density in equine hoof horn. Biomimetics 4: 23–36. doi: 10.1002/(SICI)1097-0193(1996)4:1<23::AID-HBM2>3.0.CO;2-R 20408184

18. Thomason JJ, Biewener AA, Bertram JEA (1992) Surface strin on the equine hoof wall in vivo: implications for the material design and functional morphology of the wall. J Exper Biol 166: 145–165.

19. Dyhre-Poulsen P, Smedegaard HH, Roed J, Korsgaard E (1994) Equine hoof function investigated by pressure transducers inside the hoof and accelerometers mounted on the first phalanx. Equine Vet J 26: 362–366. 7988538

20. Shendure J (2011) Next-generation human genetics. Genome Biol 12: 408. doi: 10.1186/gb-2011-12-9-408 21920048

21. Maher B (2012) ENCODE: The human encyclopaedia. Nature 489: 46–48. 22962707

22. Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, et al. (2001) The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem 276: 33293–33296. 11435447

23. Remold-O'Donnell E (1993) The ovalbumin family of serpin proteins. FEBS Lett 315: 105–108. 8417965

24. Scott FL, Eyre HJ, Lioumi M, Ragoussis J, Irving JA, et al. (1999) Human ovalbumin serpin evolution: phylogenic analysis, gene organization, and identification of new PI8-related genes suggest that two interchromosomal and several intrachromosomal duplications generated the gene clusters at 18q21-q23 and 6p25. Genomics 62: 490–499. 10644448

25. Benarafa C, Remold-O'Donnell E (2005) The ovalbumin serpins revisited: perspective from the chicken genome of clade B serpin evolution in vertebrates. Proc Natl Acad Sci U S A 102: 11367–11372. 16055559

26. Grosenbaugh DA, Hood DM (1992) Keratin and associated proteins of the equine hoof wall. Am J Vet Res 53: 1859–1863. 1280927

27. Wang Y, Guo Q, Casey A, Lin C, Chen F (2012) A new tool for conditional gene manipulation in a subset of keratin-expressing epithelia. Genesis 50: 899–907. doi: 10.1002/dvg.22046 22764128

28. Pletscher-Frankild S, Palleja A, Tsafou K, Binder JX, Jensen LJ (2014) DISEASES: Text mining and data integration of disease-gene associations. Methods.

29. Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4: e72. 16494531

30. Becker J, Semler O, Gilissen C, Li Y, Bolz HJ, et al. (2011) Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 88: 362–371. doi: 10.1016/j.ajhg.2011.01.015 21353196

31. Christiansen HE, Schwarze U, Pyott SM, AlSwaid A, Al Balwi M, et al. (2010) Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am J Hum Genet 86: 389–398. doi: 10.1016/j.ajhg.2010.01.034 20188343

32. Drogemuller C, Becker D, Brunner A, Haase B, Kircher P, et al. (2009) A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta. PLoS Genet 5: e1000579. doi: 10.1371/journal.pgen.1000579 19629171

33. Bogaert L, Van Poucke M, De Baere C, Peelman L, Gasthuys F, et al. (2006) Selection of a set of reliable reference genes for quantitative real-time PCR in normal equine skin and in equine sarcoids. BMC Biotechnol 6: 24. 16643647

34. Wickham H (2009) ggplot2: elegant graphics for data analysis. New York: Springer.

35. Team RDC (2011) R: A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria.

36. http://www.bioconductor.org/packages/release/bioc/html/qrqc.html.

37. https://github.com/ucdavis-bioinformatics/scythe.

38. Joshi NA FJ (2011) Sickle: A sliding-window, adaptive, quality-based trimming tool for FastQ files (Version 1.20) [Software]. Available at https://githubcom/najoshi/sickle

39. Li H, &Durbin R. (2009) Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25: 1754–1760. doi: 10.1093/bioinformatics/btp324 19451168

40. McKenna A, Hanna M., Banks E., Sivachenko A., Cibulskis K., Kernytsky A., Garimella K., Altshuler D., Gabriel S., Daly M., & DePristo M. A. (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Research 20: 1297–1303. doi: 10.1101/gr.107524.110 20644199

41. Auwera GA, Carneiro, M. O., Hartl, C., Poplin, R., del Angel, G., Levy‐Moonshine, A., et al. (2013) From FastQ Data to High‐Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline. Current Protocols in Bioinformatics: 11–10.

42. DePristo MA, Banks E., Poplin R., Garimella K. V., Maguire J. R., Hartl C., et al. (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature Genetics 43: 491–498. doi: 10.1038/ng.806 21478889

43. Cingolani P PA, Wang le L, Coon M, Nguyen T, et al. (2012) 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 6: 80–92. doi: 10.4161/fly.19695 22728672

44. Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, et al. (2012) Primer3—new capabilities and interfaces. Nucleic Acids Res 40: e115. 22730293

45. Fintl C, Pearson GT, Mayhew IG, Stewart Lowden C, Hopwood PA, et al. (2010) Comparative analysis of c-kit gene expression and c-Kit immunoreactivity in horses with and without obstructive intestinal disease. Vet J 186: 64–69. doi: 10.1016/j.tvjl.2009.07.015 19716327

46. Zhang YW, Davis EG, Bai J (2009) Determination of internal control for gene expression studies in equine tissues and cell culture using quantitative RT-PCR. Vet Immunol Immunopathol 130: 114–119. doi: 10.1016/j.vetimm.2009.01.012 19269038

47. Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30: e36. 11972351

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