A P387L Variant in Protein Tyrosine Phosphatase-1B (PTP-1B) Is Associated With Type 2 Diabetes and Impaired Serine Phosphorylation of PTP-1B In Vitro

  1. Søren M. Echwald1,
  2. Helle Bach1,
  3. Henrik Vestergaard2,
  4. Bjørn Richelsen3,
  5. Kurt Kristensen3,
  6. Thomas Drivsholm4,
  7. Knut Borch-Johnsen1,
  8. Torben Hansen1 and
  9. Oluf Pedersen1
  1. 1Steno Diabetes Center and Hagedorn Research Institute, Copenhagen, Denmark
  2. 2Department of Endocrinology, Herlev University Hospital, Herlev, Denmark
  3. 3Department of Medicine and Endocrinology, Aarhus, Denmark
  4. 4Centre of Preventive Medicine, Glostrup University Hospital, Glostrup, Denmark

    Abstract

    In the present study, we tested the hypothesis that variability in the protein tyrosine phosphatase-1B (PTP-1B) gene is associated with type 2 diabetes. Using single-strand conformational polymorphism analysis, we examined cDNA of PTP-1B from 56 insulin-resistant patients with type 2 diabetes as well as cDNA from 56 obese patients. Four silent variants, (NT CGA→CGG) R199R, (NT CCC→CCT) P303P, 3′UTR+104insG, and 3′UTR+86T→G, and one missense variant, P387L, were found. Subsequent analysis on genomic DNA revealed two intron variants, IVS9+57C→T and IVS9+58G→A, and two missense variants, G381S and T420M. The G381S and 3′UTR+104insG insertion variants were not associated with type 2 diabetes. In an association study, the P387L variant was found in 14 of 527 type 2 diabetic subjects (allelic frequency 1.4%, 0.4–2.4 CI) and in 5 of 542 glucose-tolerant control subjects (allelic frequency 0.5%, CI 0.1–1.1), showing a significant association to type 2 diabetes (P = 0.036). In vitro, p34 cell division cycle (p34cdc2) kinase–directed incorporation of [γ-32P]ATP was reduced in a mutant peptide compared with native peptide (387P: 100% vs. 387L: 28.4 ± 5.8%; P = 0.0012). In summary, a rare P387L variant of the PTP-1B gene is associated with a 3.7 (CI 1.26–10.93, P = 0.02) genotype relative risk of type 2 diabetes in the examined population of Danish Caucasian subjects and results in impaired in vitro serine phosphorylation of the PTP-1B peptide.

    Footnotes

    • Address correspondence and reprint requests to Søren M. Echwald, PhD, Steno Diabetes Center and Hagedorn Research Institute, Niels Steensens vej 6, DK-2820 Gentofte, Denmark. E-mail: sme{at}hagedorn.dk.

      Received for publication 20 April 2001 and accepted in revised form 31 October 2001. Posted on the World Wide Web at http://www.diabetes.org/diabetes_rapids on 11 December 2001.

      IRS, insulin receptor substrate; p34cdc2 , p34 cell division cycle; MBP, myelin basic protein; PCR, polymerase chain reaction; PTP-1B, protein tyrosine phosphatase-1B; SSCP, single-strand conformation polymorphism.

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    1. Diabetes vol. 51 no. 1 1-6
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