A new mouse model of type 2 diabetes, produced by N-ethyl-nitrosourea mutagenesis, is the result of a missense mutation in the glucokinase gene.
Here we report the first cloned N-ethyl-nitrosourea (ENU)-derived mouse model of diabetes. GENA348 was identified through free-fed plasma glucose measurement, being more than 2 SDs above the population mean of a cohort of >1,201 male ENU mutant mice. The underlying gene was mapped to the maturity-onset diabetes of the young (MODY2) homology region of mouse chromosome 11 (logarithm of odds 6.0). Positional candidate gene analyses revealed an A to T transversion mutation in exon 9 of the glucokinase gene, resulting in an isoleucine to phenylalanine change at amino acid 366 (I366F). Heterozygous mutants have 67% of the enzyme activity of wild-type littermates (P < 0.0012). Homozygous mutants have less enzyme activity (14% of wild-type activity) and are even less glucose tolerant. The GENA348 allele is novel because no mouse or human diabetes studies have described a mutation in the corresponding amino acid position. It is also the first glucokinase missense mutation reported in mice and is homozygous viable, unlike the global knockout mutations. This work demonstrates that ENU mutagenesis screens can be used to generate models of complex phenotypes, such as type 2 diabetes, that are directly relevant to human disease.
Toye
Ayo A
AA
MRC Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire OX11 0RD UK.
Moir
Lee
L
Hugill
Alison
A
Bentley
Liz
L
Quarterman
Julie
J
Mijat
Vesna
V
Hough
Tertius
T
Goldsworthy
Michelle
M
Haynes
Alison
A
Hunter
A Jacqueline
AJ
Browne
Mick
M
Spurr
Nigel
N
Cox
Roger D
RD
D000225:Adenine; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000494:pharmacology*; D005941:Glucokinase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D007532:Isoleucine; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009153:Mutagens / Q000494:pharmacology*; D020125:Mutation, Missense; D010649:Phenylalanine; D010766:Phosphorylation; D013941:Thymine
D009153:Mutagens; D007532:Isoleucine; D010649:Phenylalanine; D005941:Glucokinase; D005947:Glucose; D000225:Adenine; D005038:Ethylnitrosourea; D013941:Thymine