SEQUENCE VARIATIONS OF THE PANCREATIC-ISLET LIVER GLUCOSE-TRANSPORTER(GLUT2) GENE IN JAPANESE SUBJECTS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS

To assess the genetic susceptibility to noninsulin-dependent diabetes mellitus (NIDDM) in Japanese subjects, we investigated the role of GLU T2 gene defects in patients with NIDDM. When the allelic frequency of a simple tandem repeat polymorphism in the GLUTS gene was compared, th e allele with 155 base pairs was more common in NIDDM patients (n = 99 ) than in controls (n = 89; 5.1% vs. 0.6%; P = 0.0118, by Fisher's exa ct test), whereas this was not significant after the correction for mu ltiple comparisons. To directly identify mutations, we then analyzed e ach of 11 exons by the polymerase chain reaction-single strand conform ation polymorphism analysis in 60 NIDDM patients. We found 2 missense mutations in exon 3: CCC-->CTC (Pro(68)-->Leu) in 1 patient and ACT--> ATT(Thr(110)-->IIe) in 3 patients, all in the heterozygous state. Thes e mutations were not found in 60 control subjects. To evaluate the sig nificance of the Pro(68)-->Leu mutation, the family members of the pro band were studied. The mutation did not appear to be associated with t he disease or other clinical parameters including change in immunoreac tive insulin/change in plasma glucose or oral glucose load. The other mutation (Thr(110)-->IIe) is known to be functionally insignificant. W e identified 4 additional nucleotide changes, all of which appeared to be silent. We concluded that the mutations in the GLUTS gene were not major determinants of genetic susceptibility to NIDDM in Japanese.