title: A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program.
abstract: 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.
authors.affiliation: Mouse Functional Genomics Research Group, RIKEN Genomic Sciences Center, Kanagawa, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Inoue
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sakuraba
authors.forename: Hiromi
authors.initials: H
authors.lastname: Motegi
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Hideaki
authors.initials: H
authors.lastname: Toki
authors.forename: Junko
authors.initials: J
authors.lastname: Matsui
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Ichitomo
authors.initials: I
authors.lastname: Miwa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shigeyama
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
authors.forename: Takashi
authors.initials: T
authors.lastname: Adachi
authors.forename: Naomi
authors.initials: N
authors.lastname: Fujimoto
authors.forename: Rie
authors.initials: R
authors.lastname: Matsumoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuchihashi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kagami
authors.forename: Ayako
authors.initials: A
authors.lastname: Inoue
authors.forename: Hideki
authors.initials: H
authors.lastname: Kaneda
authors.forename: Junko
authors.initials: J
authors.lastname: Ishijima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masuya
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.forename: Osamu
authors.initials: O
authors.lastname: Minowa
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Shiroishi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D005941:Glucokinase; D005038:Ethylnitrosourea