Abstract
The nucleotide sequences of the NOD and C57BL/6J alleles of Glut-2, Sod-2, and Il-2 were determined by RT-PCR sequencing. Each of these loci is located in intervals that strongly correlated with susceptibility to diabetes in an (NOD/Uf x C57BL/6J)F1 x NOD/Uf backcross. No significant variations in the alleles of Glut-2 at 16 cM on Chromosome (Chr) 3 or Sod-2 at 8 cM on Chr 17 were detected. However, the Il-2 allele in NOD at 20 cM on Chr 3 was found to differ from that in C57BL/6J by a complex mutation involving the contraction of a simple sequence repeat (SSR). Il-2 in NOD differs from the allele in C57BL/6J via a complex mutation involving a deletion of four CAG codons from the SSR together with a length-compensatory four-codon duplication of a segment 5′ from the SSR. Two nonsynonymous mutations in the coding region 5′ to the SSR were also detected. Only these two allelic forms of Il-2 were detected in a survey of 13 standard inbred lines and 4 wild mouse strains. We propose to designate these alleles as Il-2 a (for alleles such as C57BL/6J that contain 12 CAG repeats) and Il-2 b (for alleles such as NOD), which occurred in a variety of standard inbred strains and in all four wild Mus musculus domesticus tested. The distribution of these Il-2 alleles among inbred strains correlated with the detection of Chr 3 as an interval effecting diabetes susceptibility in three separate genetic crosses. However, functional characterizations of the quantity and functional characteristics of Il-2 produced by Il-2 a and Il-2 b failed to reveal any allele-specific variations.
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References
Acha-Orbea, H., McDevitt, H.O. (1987). The first external domain of the nonobese diabetic mouse class II I-A beta chain is unique. Proc. Natl. Acad. Sci. USA 84, 2435–2439.
Asano, T., Shibasaki Y., Lin, J.-L., Akanuma, Y., Takaku, F., Oka, Y. (1989). The nucleotide sequence of cDNA for a mouse liver-type glucose transporter protein. Nucleic Acids Res. 17, 6386.
Brandhuber, B., Boone, T., Kenney, W., McKay, D. (1987). Three-dimensional structure of interleukin-2. Science 238, 1707–1709.
Cheng, Ivan C. (1992). Analysis of the multigenic inheritance of the susceptibility to diabetes in the non-obese diabetic (NOD) mouse. Dissertation. (Gainesville, Fl. University of Florida).
Chomczynski, P., Sacchi, N. (1987). Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159.
Cornall, R.J., Aitman, T.J., Hearne, C.M., Todd, J.A. (1991). The generation of a library of PCR-analyzed microsatellite variants for genetic mapping of the mouse genome. Genomics 10, 874–881.
Cornelius, Janet G., Luttge, Benjamin G., Peck, Ammon B. (1993). Antioxidant enzyme activities in IDD-prone and IDD-resistant mice: a comparative study. Free Radical Biol. Med. 14, 409–420.
Fu, Y.-H., Kuhl, D.P.A., Pizzuti, A., Pieretti, M., Sutcliffe, J.S., Richards, S., Verkerk, A.J.M.H., Holden, J.J.A., Fenwick, R.G.Jr., Warren, S.T., Oostra, B.A., Nelson, D.L., Caskey, C.T. (1991). Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67, 1047–1058.
Fu, Y.-H., Pizzuti, A., Fenwick, Jr., R1G1, King, J., Rajnarayan, S., Dunne, P.W., Dubel, J., Nasser, G.A., Ashizawa, T., de Jong, P., Wieringa, B., Korneluk, R., Perryman, M.B., Epstein, H.F., Caskey, C.T. (1992). An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256–1259.
Funahashi, M., Obata, M., Shimpo, K., Winter, W.E. (1992). Chromosome 3 GLUT2nod polymorphisms are associated with insulitis in [(NOD x NZW)F1 x NOD] backcross mice. Diabetes 41 (Suppl 1), 14A.
Hallewell, R.A., Mullenbach, G.T., Stempien, M.M., Bell, G.I. (1986). Sequence of a cDNA coding for mouse manganese superoxide dismutase. Nucleic Acids Res. 14, 9539.
Hatamori, N., Yokono, K., Nagata, M., Shii, K., Baba, S. (1990). Impaired mitogen-induced expression of high-affinity interleukin-2 receptor on spleen cells from NOD/Ski/Kbe mice. Diabetes 39, 1070–1078.
Hattori, M., Buse, J.B., Jackson, R.A., Glimcher, L., Dort, M.E., Minami, M., Makino, S., Moriwaki, K., Kuzuya, H., Imura, H., Strauss, W.M., Seidman, J.G., Eisenbarth, G.S. (1986). The NOD mouse: recessive diabetogenic gene in the major histocompatibility complex. Science 231, 733–735.
Huntington's disease collaboration group. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983.
Ikegami, H., Kawaguchi, Y., Fukuda, M., Takekawa, K., Fujioka, Y., Fujisawa, T., Ueda, H., Ogihara, T., Makino, S. (1993). Genetic mapping of MHC-linked susceptibility to IDDM utilizing intra-MHC recombinant strain. Am. Diabetes Assoc. Res. Symp. 31. (Abstract).
Kashima, N., Nishi-Takaoka, C., Fujita, T., Taki, S., Yamada, G., Hamuro, J., Taniguchi, T. (1985). Unique structure of murine interleukin-2 as deduced from cloned cDNAs. Nature 313, 402–404.
Lander, E.S., Botstein, D. (1989). Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121, 185–199.
La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E., Fischbeck, K.H. (1991). Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79.
Leiter, E.H. (1989). The genetics of diabetes susceptibility in mice. FASEB J. 3, 2231–2241.
Leiter, E.H., Serreze, D.V., Prochazka, M. (1993). A new Idd locus conferring diabetes resistance in NOR/Lt mice. Am. Diabetes Assoc. Res. Symp. 17. (Abstract)
Lund, T., O'Reilly, L., Hutchings, P., Kanagawa, O., Simpson, E., Gravely, R., Chandler, P., Dyson, J., Picard, J.K., Edwards, A., Kioussis, D., Cooke, A. (1990). Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal IE alpha-chain. Nature 345, 727–729.
Makino, S., Muraoka, Y., Kishimoto, Y., Hayashi, Y. (1985). Genetic analysis for insulitis in NOD mice. Exp. Anim. 34, 425–432.
Matsutani, A., Koranyi, L., Cox, N., Permutt, M.A. (1990). Polymorphisms of GLUT2 and GLUT4 genes: use in evaluation of genetic susceptibility to NIDDM in Blacks. Diabetes 39, 1534–1542.
McConnell, T.J., Darby, B., Wakeland, E.K. (1986). Restriction fragment-length polymorphisms of class II gene sequences in mice expressing minor structural variants of I-Ak and I-Ap. J. Immunol. 136, 3076–3084.
Meisler, M.H., Todd, J.A., Rodrigues, N., Wakeland, E.K., Seldin, M.F. (1992). Mouse chromosome 3. Mammalian Genome 3 (Suppl.), S44-S54.
Prochazka, M., Leiter, E.H., Serreze, D.V., Coleman, D.L. (1987). Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. Science 237, 286–289.
Serreze, D.V., Leiter, E.H. (1988). Defective activation of T suppressor cell function in nonobese diabetic mice. J. Immunol. 140, 3801–3807.
She, J.X., Boehme, S., Wang, T.W., Bonhomme, F., Wakeland, E.K. (1990). The generation of mhc class II gene polymorphism in the genus Mus. Biol. J. Linn. Soc. 41, 141–161.
She, J.X., Boehme, S.A., Wang, T.W., Bonhomme, F., Wakeland, E.K. (1991). Amplification of major histocompatibility complex class II gene diversity by intra-exonic recombination. Proc. Natl. Acad. Sci. USA 88, 453–457.
Silver, L.M., Artzt, K., Barlow, D., Fischer-Lindahl, K., Lyon, M.F., Klein, J., Snyder, L. (1992). Mouse chromosome 17. Mammalian Genome 3 (Suppl.), S241-S260.
Tigges, M.A., Casey, L.S., Koshland, M.E. (1989). Mechanism of interleukin-2 signaling: mediation of different outcomes by a single receptor and tranduction pathway. Science 243, 781–786.
Todd, J.A., Bell, J.I., McDevitt H.O. (1987). HLA-DQ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329, 599–604.
Todd, J.A., Aitman, T.J., Cornall, R.J., Ghosh, S., Hall, J.R.S., Hearne, C.M., Knight, A.M., Love, J.M., McAleer, M.A., Prins, J.-B., Rodrigues, N., Lathrop, M., Pressey, A., DeLarato, N.H., Peterson, L.B., Wicker, L.S. (1991). Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature 351, 542–546.
Wicker, L.S., Miller, B.J., Coker, L.Z. (1987). Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse. J. Exp. Med. 165, 1639–1654.
Wicker, L.S., Todd, J.A., Prins, J.-B., Rodrigues, N., Podolin, P.L., Renjilian, R.J., Peterson, L.B. (1993). Development of diabetes-resistant non-MHC congenic NOD mice: more than one gene on chromosome 3 from B6.PL-Thy.1a mice produces resistance to diabetes. Am. Diabetes Assoc. Res. Symp. 17. (Abstract).
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Chesnut, K., She, J.X., Cheng, I. et al. Characterizations of candidate genes for IDD susceptibility from the diabetes-prone NOD mouse strain. Mammalian Genome 4, 549–554 (1993). https://doi.org/10.1007/BF00361383
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DOI: https://doi.org/10.1007/BF00361383