J Vet Sci.  2018 Jan;19(1):129-135. 10.4142/jvs.2018.19.1.129.

Polymorphism in the serotonin transporter protein gene in Maltese dogs with degenerative mitral valve disease

Affiliations
  • 1Department of Veterinary Internal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05030, Korea. parkhee@konkuk.ac.kr
  • 2Laboratory of Wildlife Diseases, College of Veterinary Medicine, Chonbuk National University, Iksan 54596, Korea.

Abstract

Degenerative mitral valve disease (DMVD) is the most commonly acquired cardiac disease in dogs. This study evaluated the relationship between genetic variations in the serotonin transporter (SERT) gene of Maltese dogs and DMVD. Genomic DNA was extracted from blood samples collected from 20 client-owned DMVD Maltese dogs and 10 healthy control dogs, and each exon of the SERT gene was amplified via polymerase chain reaction. The resulting genetic sequences were aligned and analyzed for variations by comparing with reference sequences; the predicted secondary structures of these variations were modeled and cross-verified by applying computational methods. Genetic variations, including five nonsynonymous genetic variations, were detected in five exons. Protein structure and function of the five nonsynonymous genetic variations were predicted. Three of the five polymorphisms were predicted to be probable causes of damage to protein function and confirmed by protein structure model verification. This study identified six polymorphisms of the SERT gene in Maltese dogs with DMVD, suggesting an association between the SERT gene and canine DMVD. This is the first study of SERT mutation in Maltese dogs with DMVD and is considered a pilot study into clinical genetic examination for early DMVD diagnosis.

Keyword

canine; mitral valve; polymorphism; serotonin transporter

MeSH Terms

Animals
Diagnosis
DNA
Dogs*
Exons
Genetic Variation
Heart Diseases
Mitral Valve*
Pilot Projects
Polymerase Chain Reaction
Serotonin Plasma Membrane Transport Proteins*
Serotonin*
DNA
Serotonin
Serotonin Plasma Membrane Transport Proteins

Figure

  • Fig. 1 Predicted three-dimensional structures of serotonin transporter (SERT) proteins by using RaptorX [18]. Normal SERT structure (A) and Val397GLy variation structure (B) were visualized. The green and white portions indicate Val397 and the modified Gly397 positions, respectively. Val, valine; Gly, glycine.


Reference

1. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods. 2010; 7:248–249.
Article
2. Arndt JW, Reynolds CA, Singletary GE, Connolly JM, Levy RJ, Oyama MA. Serum serotonin concentrations in dogs with degenerative mitral valve disease. J Vet Intern Med. 2009; 23:1208–1213.
Article
3. Atkins C, Bonagura J, Ettinger S, Fox P, Gordon S, Haggstrom J, Hamlin R, Keene B, Luis-Fuentes V, Stepien R. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med. 2009; 23:1142–1150.
Article
4. Aupperle H, Disatian S. Pathology, protein expression and signaling in myxomatous mitral valve degeneration: comparison of dogs and humans. J Vet Cardiol. 2012; 14:59–71.
Article
5. Bhardwaj R, Mukhopadhyay CS, Deka D, Verma R, Dubey PP, Arora JS. Biocomputational analysis of evolutionary relationship between toll-like receptor and nucleotide-binding oligomerization domain-like receptors genes. Vet World. 2016; 9:1218–1228.
Article
6. Black A, French AT, Dukes-McEwan J, Corcoran BM. Ultrastructural morphologic evaluation of the phenotype of valvular interstitial cells in dogs with myxomatous degeneration of the mitral valve. Am J Vet Res. 2005; 66:1408–1414.
Article
7. Borgarelli M, Buchanan JW. Historical review, epidemiology and natural history of degenerative mitral valve disease. J Vet Cardiol. 2012; 14:93–101.
Article
8. Borgarelli M, Zini E, D'Agnolo G, Tarducci A, Santilli RA, Chiavegato D, Tursi M, Prunotto M, Häggström J. Comparison of primary mitral valve disease in German Shepherd dogs and in small breeds. J Vet Cardiol. 2004; 6:27–34.
Article
9. Corcoran BM, Black A, Anderson H, McEwan JD, French A, Smith P, Devine C. Identification of surface morphologic changes in the mitral valve leaflets and chordae tendineae of dogs with myxomatous degeneration. Am J Vet Res. 2004; 65:198–206.
Article
10. Cremer SE, Moesgaard SG, Rasmussen CE, Zois NE, Falk T, Reimann MJ, Cirera S, Aupperle H, Oyama MA, Olsen LH. Alpha-smooth muscle actin and serotonin receptors 2A and 2B in dogs with myxomatous mitral valve disease. Res Vet Sci. 2015; 100:197–206.
Article
11. Darmon M, Al Awabdh S, Emerit MB, Masson J. Insights into serotonin receptor trafficking: cell membrane targeting and internalization. Prog Mol Biol Transl Sci. 2015; 132:97–126.
12. Disatian S, Orton EC. Autocrine serotonin and transforming growth factor beta 1 signaling mediates spontaneous myxomatous mitral valve disease. J Heart Valve Dis. 2009; 18:44–51.
13. Drögemüller M, Jagannathan V, Becker D, Drögemüller C, Schelling C, Plassais J, Kaerle C, Dufaure de, Thomas A, Müller EJ, Welle MM, Roosje P, Leeb T. A mutation in the FAM83G gene in dogs with hereditary footpad hyperkeratosis (HFH). PLoS Genet. 2014; 10:e1004370.
Article
14. Elangbam CS, Job LE, Zadrozny LM, Barton JC, Yoon LW, Gates LD, Slocum N. 5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats. Exp Toxicol Pathol. 2008; 60:253–262.
Article
15. Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL. Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet. 1999; 88:83–87.
Article
16. Gustafsson BI, Tømmerås K, Nordrum I, Loennechen JP, Brunsvik A, Solligård E, Fossmark R, Bakke I, Syversen U, Waldum H. Long-term serotonin administration induces heart valve disease in rats. Circulation. 2005; 111:1517–1522.
Article
17. Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP. Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996; 66:2621–2624.
Article
18. Källberg M, Wang H, Wang S, Peng J, Wang Z, Lu H, Xu J. Template-based protein structure modeling using the RaptorX web server. Nat Protoc. 2012; 7:1511–1522.
Article
19. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996; 274:1527–1531.
Article
20. Levy FO, Qvigstad E, Krobert KA, Skomedal T, Osnes JB. Effects of serotonin in failing cardiac ventricle: signalling mechanisms and potential therapeutic implications. Neuropharmacology. 2008; 55:1066–1071.
Article
21. Mekontso-Dessap A, Brouri F, Pascal O, Lechat P, Hanoun N, Lanfumey L, Seif I, Benhaiem-Sigaux N, Kirsch M, Hamon M, Adnot S, Eddahibi S. Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice. Circulation. 2006; 113:81–89.
Article
22. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009; 30:2785–2791.
Article
23. Olsen LH, Fredholm M, Pedersen HD. Epidemiology and inheritance of mitral valve prolapse in Dachshunds. J Vet Intern Med. 1999; 13:448–456.
Article
24. Orton EC, Lacerda CM, MacLea HB. Signaling pathways in mitral valve degeneration. J Vet Cardiol. 2012; 14:7–17.
Article
25. Oyama MA, Chittur SV. Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease. Am J Vet Res. 2006; 67:1307–1318.
Article
26. Parker HG, Kilroy-Glynn P. Myxomatous mitral valve disease in dogs: does size matter. J Vet Cardiol. 2012; 14:19–29.
Article
27. Pedersen HD, Lorentzen KA, Kristensen BO. Echocardiographic mitral valve prolapse in cavalier King Charles spaniels: epidemiology and prognostic significance for regurgitation. Vet Rec. 1999; 144:315–320.
Article
28. Rothman RB, Baumann MH. Therapeutic and adverse actions of serotonin transporter substrates. Pharmacol Ther. 2002; 95:73–88.
Article
29. Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993; 234:779–815.
Article
30. Scruggs SM, Disatian S, Orton EC. Serotonin transmembrane transporter is down-regulated in late-stage canine degenerative mitral valve disease. J Vet Cardiol. 2010; 12:163–169.
Article
31. Sutcliffe JS, Delahanty RJ, Prasad HC, McCauley JL, Han Q, Jiang L, Li C, Folstein SE, Blakely RD. Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet. 2005; 77:265–279.
Article
32. van den Berg L, Kwant L, Hestand MS, van Oost BA, Leegwater PA. Structure and variation of three canine genes involved in serotonin binding and transport: the serotonin receptor 1A gene (htr1A), serotonin receptor 2A gene (htr2A), and serotonin transporter gene (slc6A4). J Hered. 2005; 96:786–796.
Article
33. Waraphan T, Aekkapot C, Panpanga S, Pranom P. Effect of single mutagenesis on the binding pocket of canine estrogen receptor alpha: structure and binding affinity. Adv Mod Oncol Res. 2016; 2:116–121.
Article
34. Zhao H, Yang Y, Zhou Y. Highly accurate and high-resolution function prediction of RNA binding proteins by fold recognition and binding affinity prediction. RNA Biol. 2011; 8:988–996.
Article
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