title: 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.
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 (p34(cdc2)) kinase-directed incorporation of [gamma-(32)P]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.
authors.affiliation: Steno Diabetes Center and Hagedorn Research Institute, Copenhagen, Denmark. sme@hagedorn.dk
authors.forename: Søren M
authors.initials: SM
authors.lastname: Echwald
authors.forename: Helle
authors.initials: H
authors.lastname: Bach
authors.forename: Henrik
authors.initials: H
authors.lastname: Vestergaard
authors.forename: Bjørn
authors.initials: B
authors.lastname: Richelsen
authors.forename: Kurt
authors.initials: K
authors.lastname: Kristensen
authors.forename: Thomas
authors.initials: T
authors.lastname: Drivsholm
authors.forename: Knut
authors.initials: K
authors.lastname: Borch-Johnsen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D012016:Reference Values; D012694:Serine / Q000378:metabolism*
chemical_list: D010768:Phosphoserine; D012694:Serine; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse