Type 2 (non-insulin-dependent) diabetes mellitus associated with a mutation of the glucokinase gene in a Japanese family.
Mutations were screened for in the glucokinase gene of 25 Japanese patients with Type 2 (non-insulin-dependent) diabetes mellitus. Each exon was scanned by electrophoresis of enzymatically amplified DNA segments under non-denaturing conditions and variants were sequenced. A variant pattern was detected in exon 5 of one patient. Direct sequencing of this exon revealed a single nucleotide substitution in codon 188 (GCT-->ACT) of one of two alleles resulting in the mutation of Ala188-->Thr, an invariant residue in the sequence of all mammalian glucokinases and hexokinases. This mutation was not found in 40 normal control subjects. The proband had been diagnosed with Type 2 diabetes at the age of 62 years. Four other members of her family have the same mutation and all have Type 2 diabetes or impaired glucose tolerance. The youngest age at diagnosis of Type 2 diabetes in these other members was 13 years, suggesting that her pedigree was maturity-onset diabetes of the young (MODY). All subjects with the Thr188 mutation show a decreased insulin secretory response during oral glucose tolerance testing. Mutations in the glucokinase gene associated with Type 2 diabetes have been previously identified in Caucasian (French and British) subjects. This study indicates that mutations in this gene are also implicated in the development of Type 2 diabetes in Asians. Further studies are required to determine the frequency of mutations in glucokinase among Japanese patients with Type 2 diabetes.
Shimada
F
F
Second Department of Internal Medicine, Chiba, Japan.
Makino
H
H
Hashimoto
N
N
Taira
M
M
Seino
S
S
Bell
G I
GI
Kanatsuka
A
A
Yoshida
S
S
D000293:Adolescent; D000328:Adult; D000409:Alanine; D000595:Amino Acid Sequence; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D003062:Codon / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D015226:Dinucleoside Phosphates; D005091:Exons; D005260:Female; D005941:Glucokinase / Q000235:genetics*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D013912:Threonine
D000409:Alanine; D001786:Blood Glucose; D003062:Codon; D015226:Dinucleoside Phosphates; D005941:Glucokinase; D007328:Insulin; D013912:Threonine; C015772:CpG dinucleotide