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