International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


Oral Presentation

Monday 18 November

16:00 - 16:15 HRS

IDENTIFICATION, MAPPING AND CLONING OF NEW TYPE 2 DIABETES MODELS FROM ENU MUTAGENESIS

RD Cox
Medical Research Council

Co-Authors: 1) Toye A, 1) Bentley E, 1) Goldsworthy M, 1) Moir L, 1) Mijat V, 1) Hugill A, 1) Hough T, 1) Mansell S, 1) Abdul-Hussein S, 2) Gray I, 2) Hunter J, 1) Brown SDM 
Institutions: 1) MRC, 2) GlaxoSmithKlein

Type 2 diabetes is a complex genetic disease with some rare monogenic subtypes. Disease susceptibility and progression is influenced by environmental factors. To identify new diabetes genes and develop new mouse models for basic research and for therapeutics development we identified mice with impaired glucose tolerance and diabetes in the Harwell-GSK mutagenesis programme. We initially selected 14 founder F1 (BALB/c- mutagenised x C3H) mice based on free fed blood glucose data that indicated they were >2SDs above the F1 population mean. These mice were backcrossed to C3H and their offspring tested in an intraperitoneal glucose tolerance test (IPGTT) at 12 weeks of age. Five lines survived inheritance testing with a robust IPGTT phenotype. These are GENAs 263, 348, 387, 389 and 394. All show impaired glucose tolerance in males and with the exception of GENA263 in females as well although to a lesser degree. With the exception of GENA263 BC1 males and females at 12weeks of age are statistically significantly heavier than BC1 controls. Three lines have been mapped using microsatellite markers to chromosomes 11 and 6 (the former GENA 348 and 389, the latter GENA263) and are being fine mapped. The remaining two lines are at an advanced stage of genotyping. Candidate genes have been screened for the mapped lines and we have found putative causal mutations in the two chromosome 11 mutants that appear to be alleles of each other. Further information will be presented on the details of the phenotypes and of candidate genes being investigated.


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