International Mammalian Genome Society

18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA

Plenary Presentations * Oral Presentations * Poster Abstracts * Photos
Verne Chapman Memorial Lecture * Table of Contents * Attendees * Awards

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POSTER 147- A SERIES OF MATURITY ONSET DIABETES OF THE YOUNG, TYPE 2 (MODY2) MOUSE MODELS GENERATED BY A LARGE SCALE MUTAGENESIS PROJECT IN RIKEN GSC

Inoue MI ¹, Sakuraba YS ¹, Motegi HM ¹, Kubota NK ², Terauchi YT ², Toki HT ¹, Matsui JM ¹, Toyoda YT ³, Miwa IM ³, Shigeyama YS ⁴, Kaneda HK ¹, Ishijima JI ¹, Masuya HM ¹, Suzuki TS ¹, Wakana SW ¹, Gondo YG ¹, Minowa OM ¹, Shiroishi TS ¹, Noda TN ¹

¹ RIKEN GSC, Yokohama, Japan, ² Univ. Tokyo, Tokyo, Japan, ³ Meijo Univ., Nagoya, Japan, ⁴ Kobe Univ., Kobe, Japan

In RIKEN mutagenesis project, to generate mouse models for common human diseases, we screened for various phenotypes in the mutated animals. We report here a series of new mouse models for human diabetes. 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 beta cell. Heterozygous mutations in human GK cause maturity onset diabetes of the young, type 2 (MODY2) heterozygously, and homozygous mutations result in cause permanent neonatal diabetes mellitus (PNDM). The mutations in our 11 mutant lines were, scattered　in the mouse G k k gene and, included six missense mutations, two nonsense mutations, and three mutations in splicing signals. Four lines bears 　 identical mutations to those found in human MODY2 patients, and another bears the its mutation at the same location that is mutated in a PNDM patient. All of our mutant lines displayed mildly but consistently hyperglycemia, a similar phenotype to that of human MODY2 patients, while  and the homozygotes analyzed here suffered severe hyperglycemia soon after birth, as has also been similarly reported for in human PNDM patients. 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 highly useful for understanding GK gene function, for dissecting the function of the enzyme, and as models of human MODY2 and PNDM.