Human Molecular Genetics Advance Access published online on April 21, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh133
© 2004 by Oxford University Press
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1 Mouse Functional Genomics Research Group, RIKEN Genomic Sciences Center, 214 Maeda-cho, Totsuka-ku, Yokohama, Kanagawa, 244-0804, Japan
* To whom correspondence should be addressed. E-mail: tnoda{at}ims.u-tokyo.ac.jp.
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 9,375 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
Article
A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program
2 Population and Quantitative Genomics Team, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
3 Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-3815, Japan
4 Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Aichi, 468-8503, Japan
5 Department of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan
6 Mouse Functional Genomics Research Group, RIKEN Genomic Sciences Center, 214 Maeda-cho, Totsuka-ku, Yokohama, Kanagawa, 244-0804, Japan; Mammalian Genetics Laboratory, National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan
7 Mouse Functional Genomics Research Group, RIKEN Genomic Sciences Center, 214 Maeda-cho, Totsuka-ku, Yokohama, Kanagawa, 244-0804, Japan; Department of Cell Biology, Japanese Foundation for Cancer Research (JFCR) Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-Ku, Tokyo 170-8455, Japan; Department of Functional Genomics, Division of Molecular Genetics, Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Abstract 
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.
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