A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program.
Mutant mouse models are indispensable tools for clarifying the functions of genes and for elucidating the underlying pathogenic mechanisms of human diseases. Currently, several large-scale mutagenesis projects that employ the chemical mutagen N-ethyl-N-nitrosourea (ENU) are underway worldwide. One specific aim of our ENU mutagenesis project is to generate diabetic mouse models. We screened 9375 animals for dominant traits using a clinical biochemical test and thereby identified 11 mutations in the glucokinase (Gk) gene that were associated with hyperglycemia. GK is a key regulator of insulin secretion in the pancreatic beta-cell. Approximately 190 heterozygous mutations in the human GK gene have been reported to cause maturity onset diabetes of the young, type 2 (MODY2). In addition, five mutations have been reported to cause permanent neonatal diabetes mellitus (PNDM) when present on both alleles. The mutations in our 11 hyperglycemic mutants are located at different positions in Gk. Four have also been found in human MODY2 patients, and another mutant bears its mutation at the same location that is mutated in a PNDM patient. Thus, ENU mutagenesis is effective for developing mouse models for various human genetic diseases, including diabetes mellitus. Some of our Gk mutant lines displayed impaired glucose-responsive insulin secretion and the mutations had different effects on Gk mRNA levels and/or the stability of the GK protein. This collection of Gk mutants will be valuable for understanding GK gene function, for dissecting the function of the enzyme and as models of human MODY2 and PNDM.
Inoue
Maki
M
Mouse Functional Genomics Research Group, RIKEN Genomic Sciences Center, Kanagawa, Japan.
Sakuraba
Yoshiyuki
Y
Motegi
Hiromi
H
Kubota
Naoto
N
Toki
Hideaki
H
Matsui
Junko
J
Toyoda
Yukiyasu
Y
Miwa
Ichitomo
I
Terauchi
Yasuo
Y
Kadowaki
Takashi
T
Shigeyama
Yutaka
Y
Kasuga
Masato
M
Adachi
Takashi
T
Fujimoto
Naomi
N
Matsumoto
Rie
R
Tsuchihashi
Keiko
K
Kagami
Tomoko
T
Inoue
Ayako
A
Kaneda
Hideki
H
Ishijima
Junko
J
Masuya
Hiroshi
H
Suzuki
Tomohiro
T
Wakana
Shigeharu
S
Gondo
Yoichi
Y
Minowa
Osamu
O
Shiroishi
Toshihiko
T
Noda
Tetsuo
T
D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004195:Disease Models, Animal; D005038:Ethylnitrosourea; D005260:Female; D015870:Gene Expression; D005941:Glucokinase / Q000235:genetics*; D005951:Glucose Tolerance Test; D006720:Homozygote; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010641:Phenotype; D017354:Point Mutation; D012333:RNA, Messenger / Q000032:analysis
D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D005941:Glucokinase; D005038:Ethylnitrosourea