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Mammalian Genome

, Volume 29, Issue 3–4, pp 273–280 | Cite as

Congenic mapping and candidate gene analysis for streptozotocin-induced diabetes susceptibility locus on mouse chromosome 11

  • Tomoki Maegawa
  • Yuki Miyasaka
  • Misato Kobayashi
  • Naru Babaya
  • Hiroshi Ikegami
  • Fumihiko Horio
  • Masahide Takahashi
  • Tamio Ohno
Article

Abstract

Streptozotocin (STZ) has been widely used to induce diabetes in rodents. Strain-dependent variation in susceptibility to STZ has been reported; however, the gene(s) responsible for STZ susceptibility has not been identified. Here, we utilized the A/J-11SM consomic strain and a set of chromosome 11 (Chr. 11) congenic strains developed from A/J-11SM to identify a candidate STZ-induced diabetes susceptibility gene. The A/J strain exhibited significantly higher susceptibility to STZ-induced diabetes than the A/J-11SM strain, confirming the existence of a susceptibility locus on Chr. 11. We named this locus Stzds1 (STZ-induced diabetes susceptibility 1). Congenic mapping using the Chr. 11 congenic strains indicated that the Stzds1 locus was located between D11Mit163 (27.72 Mb) and D11Mit51 (36.39 Mb). The Mpg gene, which encodes N-methylpurine DNA glycosylase (MPG), a ubiquitous DNA repair enzyme responsible for the removal of alkylated base lesions in DNA, is located within the Stzds1 region. There is a close relationship between DNA alkylation at an early stage of STZ action and the function of MPG. A Sanger sequence analysis of the Mpg gene revealed five polymorphic sites in the A/J genome. One variant, p.Ala132Ser, was located in a highly conserved region among rodent species and in the minimal region for retained enzyme activity of MPG. It is likely that structural alteration of MPG caused by the p.Ala132Ser mutation elicits increased recognition and excision of alkylated base lesions in DNA by STZ.

Notes

Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (23500494 to T. Ohno).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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References

  1. Babaya N, Ikegami H, Fujisawa T, Nojima K, Itoi-Babaya M, Inoue K, Ohno T, Shibata M, Ogihara T (2005) Susceptibility to streptozotocin-induced diabetes is mapped to mouse chromosome 11. Biochem Biophys Res Commun 328:158–164CrossRefPubMedGoogle Scholar
  2. Bhatnagar S, Oler AT, Rabaglia ME, Stapleton DS, Schueler KL, Truchan NA, Worzella SL, Stoehr JP, Clee SM, Yandell BS, Keller MP, Thurmond DC, Attie AD (2011) Positional cloning of a type 2 diabetes quantitative trait locus; tomosyn-2, a negative regulator of insulin secretion. PLoS Genet 7:e1002323CrossRefPubMedPubMedCentralGoogle Scholar
  3. Burkart V, Wang ZQ, Radons J, Heller B, Herceg Z, Stingl L, Wagner EF, Kolb H (1999) Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin. Nat Med 5:314–319CrossRefPubMedGoogle Scholar
  4. Burns N, Gold B (2007) The effect of 3-methyladenine DNA glycosylase-mediated DNA repair on the induction of toxicity and diabetes by the beta-cell toxicant streptozotocin. Toxicol Sci 95:391–400CrossRefPubMedGoogle Scholar
  5. Cardinal JW, Margison GP, Mynett KJ, Yates AP, Cameron DP, Elder RH (2001) Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice. Mol Cell Biol 21:5605–5613CrossRefPubMedPubMedCentralGoogle Scholar
  6. Choi Y, Chan AP (2015) PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31:2745–2477CrossRefPubMedPubMedCentralGoogle Scholar
  7. Clee SM, Yandell BS, Schueler KM, Rabaglia ME, Richards OC, Raines SM, Kabara EA, Klass DM, Mui ET, Stapleton DS, Gray-Keller MP, Young MB, Stoehr JP, Lan H, Boronenkov I, Raess PW, Flowers MT, Attie AD (2006) Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Nat Genet 38:688–693CrossRefPubMedGoogle Scholar
  8. Daimon M, Oizumi T, Toriyama S, Karasawa S, Jimbu Y, Wada K, Kameda W, Susa S, Muramatsu M, Kubota I, Kawata S, Kato T (2009) Association of the Ser326Cys polymorphism in the OGG1 gene with type 2 DM. Biochem Biophys Res Commun 386:26–29CrossRefPubMedGoogle Scholar
  9. Dooley J, Tian L, Schonefeldt S, Delghingaro-Augusto V, Garcia-Perez JE, Pasciuto E, Di Marino D, Carr EJ, Oskolkov N, Lyssenko V, Franckaert D, Lagou V, Overbergh L, Vandenbussche J, Allemeersch J, Chabot-Roy G, Dahlstrom JE, Laybutt DR, Petrovsky N, Socha L, Gevaert K, Jetten AM, Lambrechts D, Linterman MA, Goodnow CC, Nolan CJ, Lesage S, Schlenner SM, Liston A (2016) Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes. Nat Genet 48:519–527CrossRefPubMedPubMedCentralGoogle Scholar
  10. Festing MF (1996) Origins and characteristics of inbred strains of mice. In: Lyon MF, Rasten S, Brown SDM (eds) Genetic variants and strains of the laboratory mouse. Oxford University Press, New York, pp 1537–1576Google Scholar
  11. Gonzalez C, Cuvellier S, Hue-Beauvais C, Lévi-Strauss M (2003) Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes. Diabetologia 46:1291–1295CrossRefPubMedGoogle Scholar
  12. Hada N, Kobayashi M, Fujiyoshi M, Ishikawa A, Kuga M, Nishimura M, Ebihara S, Ohno T, Horio F (2008) Quantitative trait loci for impaired glucose tolerance in nondiabetic SM/J and A/J mice. Physiol Genomics 35:65–74CrossRefPubMedGoogle Scholar
  13. Hadjivassiliou V, Green MH, James RF, Swift SM, Clayton HA, Green IC (1998) Insulin secretion, DNA damage, and apoptosis in human and rat islets of Langerhans following exposure to nitric oxide, peroxynitrite, and cytokines. Nitric Oxide 2:429–441CrossRefPubMedGoogle Scholar
  14. Kaku K, Fiedorek FT Jr, Province M, Permutt MA (1988) Genetic analysis of glucose tolerance in inbred mouse strains: evidence for polygenic control. Diabetes 37:707–713CrossRefPubMedGoogle Scholar
  15. Kaku K, McGill J, Province M, Permutt MA (1989) A single major gene controls most of the difference in susceptibility to streptozotocin-induced diabetes between C57BL/6J and C3H/HeJ mice. Diabetologia 32:716–723CrossRefPubMedGoogle Scholar
  16. Kikutani H, Makino S (1992) The murine autoimmune diabetes model: NOD and related strains. Adv Immunol 51:285–322CrossRefPubMedGoogle Scholar
  17. Kobayashi M, Ohno T, Hada N, Fujiyoshi M, Kuga M, Nishimura M, Murai A, Horio F (2010) Genetic analysis of abdominal fat distribution in SM/J and A/J mice. J Lipid Res 51:3463–3469CrossRefPubMedPubMedCentralGoogle Scholar
  18. Kolb H (1987) Mouse models of insulin dependent diabetes: low-dose streptozocin-induced diabetes and nonobese diabetic (NOD) mice. Diabetes Metab Rev 3:751–778CrossRefPubMedGoogle Scholar
  19. Lenzen S (2008) The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51:216–226CrossRefPubMedGoogle Scholar
  20. Liston A, Todd JA, Lagou V (2017) Beta-cell fragility as a common underlying risk factor in type 1 and type 2 diabetes. Trends Mol Med 23:181–194CrossRefPubMedGoogle Scholar
  21. Masutani M, Suzuki H, Kamada N, Watanabe M, Ueda O, Nozaki T, Jishage K, Watanabe T, Sugimoto T, Nakagama H, Ochiya T, Sugimura T (1999) Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes. Proc Natl Acad Sci USA 96:2301–2304CrossRefPubMedPubMedCentralGoogle Scholar
  22. Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24:221–225CrossRefPubMedGoogle Scholar
  23. Nishimura M, Hirayama N, Serikawa T, Kanehira K, Matsushima Y, Katoh H, Wakana S, Kojima A, Hiai H (1995) The SMXA: a new set of recombinant inbred strain of mice consisting of 26 substrains and their genetic profile. Mamm Genome 6:850–857CrossRefPubMedGoogle Scholar
  24. Ohno T, Hata K, Baba T, Io F, Kobayashi M, Horio F, Nishimura M (2012) Establishment of consomic strains derived from A/J and SM/J mice for genetic analysis of complex traits. Mamm Genome 23:764–769CrossRefPubMedGoogle Scholar
  25. Pataer A, Nishimura M, Kamoto T, Ichioka K, Sato M, Hiai H (1997) Genetic resistance to urethan-induced pulmonary adenomas in SMXA recombinant inbred mouse strains. Cancer Res 57:2904–2908PubMedGoogle Scholar
  26. Pieper AA, Brat DJ, Krug DK, Watkins CC, Gupta A, Blackshaw S, Verma A, Wang ZQ, Snyder SH (1999) Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Proc Natl Acad Sci USA 96:3059–3064CrossRefPubMedPubMedCentralGoogle Scholar
  27. Rogner UC, Avner P (2003) Congenic mice: cutting tools for complex immune disorders. Nat Rev Immunol 3:243–252CrossRefPubMedGoogle Scholar
  28. Rossini AA, Appel MC, Williams RM, Like AA (1977) Genetic influence of the streptozotocin-induced insulitis and hyperglycemia. Diabetes 26:916–920CrossRefPubMedGoogle Scholar
  29. Roy R, Kumar A, Lee JC, Mitra S (1996) The domains of mammalian base excision repair enzyme N-methylpurine-DNA glycosylase. Interaction, conformational change, and role in DNA binding and damage recognition. J Biol Chem 271:23690–23697CrossRefPubMedGoogle Scholar
  30. Roy R, Biswas T, Hazra TK, Roy G, Grabowski DT, Izumi T, Srinivasan G, Mitra S (1998) Specific interaction of wild-type and truncated mouse N-methylpurine-DNA glycosylase with ethenoadenine-containing DNA. Biochemistry 37:580–589CrossRefPubMedGoogle Scholar
  31. Singer JB, Hill AE, Burrage LC, Olszens KR, Song J, Justice M, O’Brien WE, Conti DV, Witte JS, Lander ES, Nadeau JH (2004) Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304:445–448CrossRefPubMedGoogle Scholar
  32. Stylianou IM, Clinton M, Keightley PD, Pritchard C, Tymowska-Lalanne Z, Bunger L, Horvat S (2005) Microarray gene expression analysis of the Fob3b obesity QTL identifies positional candidate gene Sqle and perturbed cholesterol and glycolysis pathways. Physiol Genomics 20:224–232CrossRefPubMedGoogle Scholar
  33. Szkudelski T (2012) Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med 237:481–490CrossRefGoogle Scholar
  34. Takada T, Mita A, Maeno A, Sakai T, Shitara H, Kikkawa Y, Moriwaki K, Yonekawa H, Shiroishi T (2008) Mouse inter-subspecific consomic strains for genetic dissection of quantitative complex traits. Genome Res 18:500–508CrossRefPubMedPubMedCentralGoogle Scholar
  35. Tanaka S, Mizorogi T, Nishijima K, Kuwahara S, Tsujio M, Aoyama H, Taguchi C, Kobayashi M, Horio F, Ohno T (2009) Body and major organ weights of A/J-Chr11SM consomic mice. Exp Anim 58:357–361CrossRefPubMedGoogle Scholar
  36. Thameem F, Puppala S, Lehman DM, Stern MP, Blangero J, Abboud HE, Duggirala R, Habib SL (2009) The Ser(326)Cys polymorphism of 8-oxoguanine glycosylase 1 (OGG1) is associated with type 2 diabetes in Mexican Americans. Hum Hered 70:97–101CrossRefGoogle Scholar
  37. Ueda H, Ikegami H, Yamato E, Fu J, Fukuda M, Shen G, Kawaguchi Y, Takekawa K, Fujioka Y, Fujisawa T, Nakagawa Y, Hamada Y, Shibata M, Ogihara T (1995) The NSY mouse: a new animal model of spontaneous NIDDM with moderate obesity. Diabetologia 38:503–508CrossRefPubMedGoogle Scholar
  38. Wyatt MD, Allan JM, Lau AY, Ellenberger TE, Samson LD (1999) 3-Methyladenine DNA glycosylases: structure, function, and biological importance. Bioessays 21:668–676CrossRefPubMedGoogle Scholar
  39. Yamamoto H, Uchigata Y, Okamoto H (1981) Streptozotocin and alloxan induce DNA strand breaks and poly(ADP-ribose)synthetase in pancreatic islets. Nature 294:284–286CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Tomoki Maegawa
    • 1
  • Yuki Miyasaka
    • 1
  • Misato Kobayashi
    • 2
  • Naru Babaya
    • 3
  • Hiroshi Ikegami
    • 3
  • Fumihiko Horio
    • 2
  • Masahide Takahashi
    • 4
  • Tamio Ohno
    • 1
  1. 1.Division of Experimental Animals, Graduate School of MedicineNagoya UniversityNagoyaJapan
  2. 2.Department of Applied Molecular Bioscience, Graduate School of Bioagricultural SciencesNagoya UniversityNagoyaJapan
  3. 3.Department of Endocrinology, Metabolism and DiabetesKindai University Faculty of MedicineOsaka-sayamaJapan
  4. 4.Department of Pathology, Graduate School of MedicineNagoya UniversityNagoyaJapan

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