Diabetologia

, Volume 39, Issue 6, pp 725–730 | Cite as

Searching for NIDDM susceptibility genes: studies of genes with triplet repeats expressed in skeletal muscle

  • K. Yamagata
  • J. Takeda
  • S. Menzel
  • X. Chen
  • S. Eng
  • L. R. Lim
  • P. Concannon
  • C. L. Hanis
  • R. S. Spielman
  • N. J. Cox
  • G. I. Bell
Originals

Summary

The expansion of trinucleotide repeats has been associated with late-onset neurodegenerative disorders. Although the genes harbouring the triplet expansions may be widely expressed, the pathological expression of these diseases is restricted to specific tissues. Non-insulin-dependent diabetes mellitus (NIDDM) shares several features with diseases resulting from such dynamic mutations including late-onset and specific but limited sites of tissue pathology — muscle, fat, liver and insulin-secreting pancreatic beta cells. In order to examine the contribution of genes containing polymorphic CAG/CTG repeats to the development of NIDDM, we screened an adult human skeletal muscle cDNA library for expressed sequences containing tandem repeats of CAG and/or CTG. Ten different loci with polymorphic CAG/CTG repeats were identified, of which seven had a heterozygosity greater than 0.20. There was no evidence for linkage between these seven loci and NIDDM in a group of affected Mexican-American sib pairs. Nor was there a significant difference in the distribution of alleles between Caucasian patients with NIDDM and normal healthy control subjects or evidence for repeat expansion in diabetic subjects. Thus, muscle genes with polymorphic CAG/CTG repeats do not appear to play a significant role in the development of NIDDM.

Keywords

Diabetes mellitus insulin resistance genetics linkage analysis 

Abbreviations

NIDDM

Non-insulin-dependent diabetes mellitus

MODY

maturity onset diabetes of the young

PCR

polymerase chain reaction

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    DeFronzo RA, Bonadonna RC, Ferrannini E (1992) Pathogenesis of NIDDM: a balanced overview. Diabetes Care 15: 318–368CrossRefPubMedGoogle Scholar
  2. 2.
    Turner RC, Hattersley AT, Shaw JTE, Levy JC (1995) Type II diabetes: clinical aspects of molecular biological studies. Diabetes 44: 1–10CrossRefPubMedGoogle Scholar
  3. 3.
    Steiner DF, Tager HS, Nanjo K, Chan SJ, Rubenstein AH (1995) Familial syndromes of hyperproinsulinemia and hyperinsulinemia with mild diabetes. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 7th edn. McGraw-Hill, New York, pp 897–904Google Scholar
  4. 4.
    Taylor SI (1995) Diabetes mellitus. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 7th edn. McGraw-Hill, New York, pp 843–896Google Scholar
  5. 5.
    Bell GI, Xiang K-S, Newman MV et al. (1991) Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on chromosome 20q. Proc Natl Acad Sci USA 88: 1484–1488CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Froguel P, Vaxillaire M, Sun F et al. (1992) Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356: 162–164CrossRefPubMedGoogle Scholar
  7. 7.
    Hattersley AT, Turner RC, Permutt MA et al. (1992) Linkage of type 2 diabetes to the glucokinase gene. Lancet 339: 1307–1310CrossRefPubMedGoogle Scholar
  8. 8.
    Vaxillaire M, Boccio V, Philippi A et al. (1995) A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nature Genet 9: 418–423CrossRefPubMedGoogle Scholar
  9. 9.
    Prochazka M, Lillioja S, Tait JF et al. (1993) Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians. Diabetes 42: 514–519CrossRefPubMedGoogle Scholar
  10. 10.
    Thompson DB, Janssen RC, Ossowski VM, Prochazka M, Knowler WC, Bogardus C (1995) Evidence for linkage between a region on chromosome 1p and the acute insulin response in Pima Indians. Diabetes 44: 478–481CrossRefPubMedGoogle Scholar
  11. 11.
    Willems PJ (1994) Dynamic mutations hit double figures. Nature Genet 8: 213–215CrossRefPubMedGoogle Scholar
  12. 12.
    Rotter JI, Vadheim CM, Rimoin DL (1990) Genetics of diabetes mellitus. In: Rifkin H, Porte D (eds) Diabetes mellitus, theory and practice, 4th edn. Elsevier, New York, pp 378–413Google Scholar
  13. 13.
    Riggins GJ, Lokey LK, Chastain JL et al. (1992) Human genes containing polymorphic trinucleotide repeats. Nature Genet 2: 186–191CrossRefPubMedGoogle Scholar
  14. 14.
    Blackman MR, Elahi D, Harman SM (1995) Endocrinology and aging. In: DeGroot LJ (ed) Endocrinology. 3rd edn, WB Saunders, Philadelphia, pp 2702–2730Google Scholar
  15. 15.
    Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215: 404–410CrossRefGoogle Scholar
  16. 16.
    Bell GI, Horita S, Karam JH (1984) A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33: 176–183CrossRefPubMedGoogle Scholar
  17. 17.
    Hanis CL, Barton SA, Chu H-H, Schull WJ, Lawson K, Garcia CA, Hewett-Emmett D (1993) Mortality of Mexican Americans with NIDDM: retinopathy and other predictors in Starr County, Texas. Diabetes Care 16: 82–89CrossRefPubMedGoogle Scholar
  18. 18.
    Bishop DT, Williamson JA (1990) The power of identity-by-state methods for linkage analysis. Am J Hum Genet 46: 254–265PubMedPubMedCentralGoogle Scholar
  19. 19.
    Holmans P (1993) Asymptotic properties of affected-sib-pair linkage analysis. Am J Hum Genet 52: 362–374PubMedPubMedCentralGoogle Scholar
  20. 20.
    Holmans P, Clayton D (1995) Efficiency of typing unaffected relatives in an affected-sib-pair linkage study with single-locus and multiple tightly linked markers. Am J Hum Genet 57: 1221–1232PubMedPubMedCentralGoogle Scholar
  21. 21.
    Hudson TJ, Stein LD, Gerety SS et al. (1995) An STS-based map of the human genome. Science 270: 1945–1954CrossRefPubMedGoogle Scholar
  22. 22.
    Fasman KH, Cuticchia AJ, Kingsbury DT (1994) The GDB human genome data base 1994. Nucl Acids Res 22: 3462–3469CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • K. Yamagata
    • 1
  • J. Takeda
    • 1
  • S. Menzel
    • 1
  • X. Chen
    • 1
  • S. Eng
    • 1
  • L. R. Lim
    • 1
  • P. Concannon
    • 2
  • C. L. Hanis
    • 3
  • R. S. Spielman
    • 4
  • N. J. Cox
    • 1
  • G. I. Bell
    • 1
  1. 1.Howard Hughes Medical Institute, and Departments of Biochemistry and Molecular Biology and MedicineThe University of ChicagoChicagoUSA
  2. 2.Virginia Mason Research CenterSeattleUSA
  3. 3.Human Genetics CenterThe University of Texas Health Science CenterHoustonUSA
  4. 4.Department of GeneticsUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations