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
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
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. / Echwald, Søren M; Riis, Helle Bach; Vestergaard, Henrik; Richelsen, Bjørn; Kristensen, Kurt; Drivsholm, Thomas; Borch-Johnsen, Knut; Hansen, Torben; Pedersen, Oluf.
In: Diabetes, Vol. 51, No. 1, 01.01.2002, p. 1-6.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - 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
AU - Echwald, Søren M
AU - Riis, Helle Bach
AU - Vestergaard, Henrik
AU - Richelsen, Bjørn
AU - Kristensen, Kurt
AU - Drivsholm, Thomas
AU - Borch-Johnsen, Knut
AU - Hansen, Torben
AU - Pedersen, Oluf
PY - 2002/1/1
Y1 - 2002/1/1
N2 - 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.
AB - 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.
KW - Amino Acid Substitution
KW - Animals
KW - Diabetes Mellitus, Type 2
KW - Female
KW - Genetic Variation
KW - Genotype
KW - Humans
KW - Male
KW - Mice
KW - Middle Aged
KW - Phosphorylation
KW - Phosphoserine
KW - Polymerase Chain Reaction
KW - Protein Tyrosine Phosphatase, Non-Receptor Type 1
KW - Protein Tyrosine Phosphatases
KW - Reference Values
KW - Serine
M3 - Journal article
C2 - 11756316
VL - 51
SP - 1
EP - 6
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 1
ER -
ID: 33030741