| First Author | Weinshilboum RM | Year | 1992 |
| Journal | Mouse Genome | Volume | 90 |
| Issue | 3 | Pages | 446-48 |
| Mgi Jnum | J:2538 | Mgi Id | MGI:51060 |
| Citation | Weinshilboum RM, et al. (1992) Tpmt and Ly-28: localization of mouse chromosome 13. Mouse Genome 90(3):446-48 |
| abstractText | Full text of Mouse Genome contribution: Tpmt AND Ly-28: LOCALIZATION ON MOUSE CHROMOSOME. Richard M. Weinshilboum, M.D.1, Diane M. Otterness, B.S.1, Nobuhiko Tada, M.D.2 and Benjamin A. Taylor, Ph.D.3; 1Clinical Pharmacology Unit, Department of Pharmacology, Mayo Foundation/Mayo Clinic, Rochester, MN 55905 USA; 2Department of Pathology, School o f Medicine, Tokai University, Boheseidai, Isehara, Japan; 3The Jackson Laboratory, Bar Harbor, ME 04609 USA. INTRODUCTION Thiopurine methyltransferase (TPMT, EC 2.1.1.67) catalyzes the S-methylation of thiopurine drugs such as azathioprine and 6-mercaptopurine (6-MP)1, 2. TPMT activity in human tissues is controlled by a common genetic polymorphism3. Inherited variation in TPMT activity is a major factor responsible for individual differences in thiopurine drug toxicity and therapeutic efficacy in humans4, 5, 6. Thiopurine drugs are widely used in the treatment of neoplastic diseases such as acute lymphoblastic leukemia of childhood, but, because of their toxicity, it was important that an experimental animal model for "pharmacogenetic" variation i n TPMT activity be developed for use in pharmacologic and toxicologic experiments. When 10 inbred strains of mice were studied, both male and female C57BL/6J, C57BL/6ByJ and AKR/J mice were found to have TPMT enzyme activity levels in hepatic and renal tissue approximately 25% and 50% respectively, of those in tissue from the other 7 inbred strains studied. Breeding studies conducted with C57BL/6J, AKR/J and a high activity strain, DBA/2J, demonstrated that the level of TPMT activity in these animals was inherited in a mendelian fashion, with low activity segregating as an autosomal recessive trait8. The locus involved, Tpmt, was identical in AKR/J and C57BL/6J mice, although it could not be determined whether the alleles for low activity in the two strains were identical8. The results of segregation analysis were confirmed by studies of recombinant inbred (RI) AKXD and BXD mice. Those studies demonstrated that 12 of 23 AKXD strains were of the low activity phenotype while 11 of 25 BXD strains had low TPMT activity9. A comparison of these strain distribution patterns (SDP) with those available at that time for other loci demonstrated that Tpmt was closely linked to Ly-28, a locus regulating a lymphocyte alloantigen10. Unfortunately, because the chromosomal location of Ly-28 was not known, the localization of Tpmt also remained unknown9. However, as a result of the subsequent accumulation o f SDP data for additional loci in AKXD and BXD RI strains, we are now able to report that both Tpmt and Ly-28 are located on the middle portion of mouse chromosome 13. METHODS SDPs for Tpmt in 23 AKXD and 25 BXD RI strains were compared with a database of previously typed loci in these RI strains maintained by one of us, (BAT) at The Jackson Laboratory, Bar Harbor, ME. Estimated recombination frequencies were calculated by use of the equation r = R/(4-6R)11. In this equation r is the estimated recombination frequency, and R is the observed proportion of RI strains with recombinant genotypes. The 95% confidence limits for estimates of recombination frequencies were obtained from tables of the binomial distributions. RESULTS A comparison of AKXD SDPs for Tpmt and Ly-28 with those of 3 loci known to be located on mouse chromosome 13 are shown i n Table 1. T p t and Ly-28 showed high concordance with D13Nds1, a locus located near the middle of chromosome 13(12). There was only a small increase in discordance for Pmv-41, another chromosome 13 locus(13, 14). We reported previously that Tpmt and Ly-28 appeared to be tightly linked since no crossovers were present among the 13 AKXD RI strains in which both loci had been typed9. The results obtained with AKXD animals were confirmed by comparison of Tpmt SDPs for BXD RI mice with those of 4 loci known to be located on chromosome 13 (Table 2). In this case, there was marginally significant concordance between Tpmt and both Ms6-1 and Pmv-41 (13, 14), with increasing discordance with SDPs for loci further from the middle of chromosome 13. Estimated recombination frequencies, with 95% confidence 1imits, for the four loci most closely linked with Tpmt in these two sets of RI strains were: Ly-28, 0.0 (0.0-0.074), D13Nds1, 0.041 (0.0072-0.17); Ms6-1, 0.081 (0.021-0.32); and Pmv-41, 0.087 (0.038-0.19), respectively. Therefore, SDP data from both AKXD and BXD RI mice were compatible with the conclusion that Tpmt and Ly-28 were located near the middle of mouse chromosome 13. TABLE 1. Locus: Xmv-27; Reference: 12; AKXD Strain: 1:A*; 2:D*; 3:A; 6:D*; 7:D*; 8:D; 9:D; 10:D; 11:A; 12:A; 13:D; 14:A*; 15:D; 16:A; 17:D; 18:D; 20:D*; 21:A*; 22:D*; 23:A; 24:A; 25:D; 26:D*; 27:D; 28:A*; Discordant/Total: 10/23a. Locus: Ly-28; Reference: 9; AKXD Strain: 1:D; 8:D; 9:D; 10:D; 11:A; 13:D; 14:D; 16:A; 21:D; 23:A; 25:D; 27:D; 28:D; Discordant/Total: 0/13. Locus: Tpmt; Reference: 9; AKXD Strain: 1:D; 2:A; 3:A*; 6:A; 7:A; 8:D; 9:D*; 10:D; 11:A; 12:A; 13:D; 14:D; 16:A; 18:D; 20:A; 21:D; 22:A*; 23:A; 24:A; 25:D; 26:A; 27:D; 28:D; Discordant/Total: 3/23. Locus: D13Nds1; Reference: 12; AKXD Strain: 1:D; 2:A; 3:D; 6:A; 7:A; 8:D; 9:A; 10:D; 11:A; 12:A; 13:D; 14:D*; 15:D;16:A; 18:D; 20:A*; 21:D; 22:D; 23:A; 24:A; 25:D; 26:A; 27:D; 28:D*; Discordant/Total: 3/24. Locus: Pmv-41; Reference: 13, 14; AKXD Strain: 1:D; 2:A; 3:D; 6:A; 7:A; 8:D; 9:A; 10:D; 11:A; 12:A; 13:D; 14:A; 15:D;16:A; 17:A; 18:D; 20:D; 21:D; 22:D; 23:A; 24:A; 25:D; 26:A; 27:D; 28:A; Discordant/Total: 3/24. Table 1. (Legend). SDPs for AKXD RI strains. The letters "A" and ÒDÓ are used to denote alleles inherited from the AKR/J and DBA/2J progenitor strains, respectively. Asterisks represent discordance between successive loci. (a)The comparison for Xmv-27 is with the Tpmt SDP. TABLE 2. Locus: Hist1; Reference: 19; BXD Strain: 1:D*; 2:B*; 5:B*; 6:B; 8:B; 9:B*; 11:B*; 12:D; 13:D; 14:D*; 15:B; 16:B*; 18:D*; 19:B; 20:B; 21:B*; 22:B; 23:D*; 24:B; 25:D; 27:D; 28:B*; 29:D*; 30:B*; 31:D; 32:D; Discordant/Total: 13/25. Locus: Tpmt; Reference: 9; BXD Strain: 1:B; 2:D; 5:D*; 6:B*; 8:B; 9:D; 11:D*; 12:D; 13:D; 14:B*; 15:B; 16:D; 18:B; 19:B; 21:D; 22:B; 23:B; 24:B*; 25:D; 27:D; 28:D; 29:B; 30:D; 31:D; 32:D; Discordant/Total: 5/23. Locus: Ms6-1; Reference: 15; BXD Strain: 1:B; 2:D; 5:B; 6:D; 8:B; 9:D; 11:B*; 12:D; 13:D; 14:D; 15:B; 16:D; 19:B; 20:D; 21:D; 22:B; 24:D; 25:D; 27:D; 28:D; 29:B; 30:D; 31:D; 32:D; Discordant/Total: 1/24. Locus: Pmv-41; Reference: 13, 14; BXD Strain: 1:B*; 2:D; 5:B; 6:D; 8:B; 9:D; 11:D; 12:D; 13:D; 14:D; 15:B*; 16:D; 18:B; 19:B; 20:D; 21:D; 22:B; 23:D; 24:D; 25:D; 27:D; 28:D; 29:B; 30:D; 31:D*; 32:D; Discordant/Total: 3/26. Locus: Xmv-13; Reference: 18; BXD Strain: 1:D; 2:D; 5:B; 6:D; 8:B; 9:D; 11:D; 12:D; 13:D; 14:D; 15:D; 16:D; 18:B; 19:B; 20:D; 21:D; 22:B; 23:D; 24:D; 25:D; 27:D; 28:D; 29:B; 30:D; 31:B; 32:D. Table 2. (Legend). SDPs for BXD RI strains. The letters ÒBÓ and "D" are used to denote alleles inherited from the C57BL/6J and DBA/2J progenitor strains, respectively. Asterisks represent discordance between successive loci. CONCLUSION Comparisons of SDPs for the genetically polymorphic locus Tpmt with those of other polymorphic loci in two different sets of RI mice were compatible with the localization of Tpmt near the middle of chromosome 13. Since the lymphocyte alloantigen locus Ly-28 was shown previously to be very tightly linked to Tpmt9 , these results were also compatible with the conclusion that Ly-28 was localized to the mid-portion of chromosome 13. In an earlier publication, Ly-28 was reported to be located on chromosome 2(16). However, we have been unsuccessfu1 in our attempts to verify the data quoted in support of that reported localization(17). Therefore, on the basis of the results of studies of SDPs for RI mice, we conclude that both Tpmt and Ly-28 are localized to the middle portion of mouse chromosome 13. Acknowledgement We thank Luanne Wussow for her assistance with the preparation of this report. 1. Remy CN. J Biol Cham 1980;238:1078-1084. 2. Woodson LC and Weinshilboum RM. Biochem Pharmacol 1983; 32:819-826. 3. Weinshilboum RM and Sladek SL. Amer J Human Genet 1980; 2:651-662. 4. Lennard L, Van Loon JA, Lilleyman JS and Weinshilboum RM. Clin Pharmacol Ther 1987; 41:18-25. 5. Lennard L, Van Loon JA and Weinshilboum RM. Clin Pharmacol Ther 1989;46:149-154. 6. Leonard L, Lilleyman JS, Van Loon J and Weinshilboum RM. Lancet 1990; 336:225-229. 7. Otterness DM, Keith RA and Weinshilboum RM. Biochem Pharmacol 1985; 34:3823-3830. 8. Otterness DM and Weinshilboum RM. J Pharmacol Exp Ther 1987; 240:817-824. 9. Otterness DM and Weinshilboum RM. J Pharmacol Exp Ther 1987; 243:180-186. 10. Tada N, Tamaoki N, Ikegami S, Nakamura S, Dairiki K and Fujimori T. Immunogenetics 1986; 24: 275-277. 11. Taylor BA. In: HC Morse III ed. Origins of Inbred Mice. Academic Press, New York, 1978:423-438. 12. Cornall RJ, Aitman TJ, Hearne CM and Todd JA. Genomics 1991; 10:874-881. 13. Frankel WN, Stoye JP, Taylor BA and Coffin JM. J Virol. 1989; 63:3810-3812. 14. Frankel WN and Coffin JM. Mouse Genome 1991; 89:848. 15. Jeffreys AJ, Wilson V, Kelly R, Taylor BA and Bulfield G. Nucleic Acids Res 1987; 15:2823-2836. 16. Holmes KL and Morse III HC. Immunol Today 1988; 9:344-350. 17. Morse III HC, Shen F-W and Hammerling U. Immunogenetics 1987; 25:71-78. 18. Frankel WN and Coffin JM. J Virol 1989; 63:1763-1774. 19. Owen FL, Taylor BA, Sweidler A and Seidman JG. J lmmunol 1986; 137:1044-1046. This work was supported in part by NIH grants GM 28157 (RMW), GM 35720 (RMW) and GM 18684 (BAT). |
