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Several mutant mouse models for human diseases such as diabetes mellitus have been generated in the large-scale Munich ENU (N-ethyl-N-nitrosourea) mouse mutagenesis project. The aim of this study was to identify the causal mutation of one of these strains and to characterize the resulting diabetic phenotype. Mutants exhibit a T to G transversion mutation at nt 629 in the glucokinase (Gck) gene, leading to an amino acid exchange from methionine to arginine at position 210. Adult Munich GckM210R mutant mice demonstrated a significant reduction of hepatic glucokinase enzyme activity but equal glucokinase mRNA and protein abundances. While homozygous mutant mice exhibited growth retardation and died soon after birth in consequence of severe hyperglycemia, heterozygous mutant mice displayed only slightly elevated blood glucose levels, present from birth, with development of disturbed glucose tolerance and glucose-induced insulin secretion. Additionally, insulin sensitivity and fasting serum insulin levels were slightly reduced in male mutant mice from an age of 90 days onward. While β-cell mass was unaltered in neonate heterozygous and homozygous mutant mice, the total islet and β-cell volumes and the total volume of isolated β-cells were significantly decreased in 210-day-old male, but not female heterozygous mutant mice despite undetectable apoptosis. These findings indicate that reduced total islet and β-cell volumes of male mutants might emerge from disturbed postnatal islet neogenesis. Considering the lack of knowledge about the pathomorphology of maturity-onset diabetes of the young type 2 (MODY 2), this glucokinase mutant model of reduced total islet and total β-cell volume provides the opportunity to elucidate the impact of a defective glucokinase on development and maintenance of 13-cell mass and its relevance in MODY 2 patients. [ABSTRACT FROM AUTHOR]

Amelogenesis imperfecta is an inherited disorder affecting tooth enamel formation. We previously isolated a mouse strain with an amelogenesis imperfecta phenotype (ATE1 mice) from a dominant ethylnitrosourea screen and mapped the disease-causing defect to a 9-cM region of mouse chromosome 5. In the current study, we tested the hypothesis that there is a mutation in enamelin (ENAM) or ameloblastin (AMBN), both of which are located wihin the linkage region, by sequencing these two candidate genes. Analysis of our data shows that the amelogenesis imperfecta phenotype is linked to a C > T transition in exon 8 of the enamelin gene. The mutation predicts a C826T transition, which is present in the enamelin transcript and changes the glutamine (Gln) codon at position 176 into a premature stop codon (Gln176X). Conversely, no mutation could be detected in the ameloblastin gene. These results define the ATE1 mice as a model for local hypoplastic autosomal-dominant amelogenesis imperfecta (AIH2), which is caused by enamelin truncation mutations in humans [ABSTRACT FROM AUTHOR]

The novel diabetic mouse model Munich Ins2(C95S) was discovered within the Munich N-ethyl-N-nitrosourea mouse mutagenesis screen. These mice exhibit a T-->A transversion in the insulin 2 (Ins2) gene at nucleotide position 1903 in exon 3, which leads to the amino acid exchange C95S and loss of the A6-A11 intrachain disulfide bond. From 1 month of age onwards, blood glucose levels of heterozygous Munich Ins2(C95S) mutant mice were significantly increased compared with controls. The fasted and postprandial serum insulin levels of the heterozygous mutants were indistinguishable from those of wild-type littermates. However, serum insulin levels after glucose challenge, pancreatic insulin content, and homeostasis model assessment (HOMA) beta-cell indices of heterozygous mutants were significantly lower than those of wild-type littermates. The initial blood glucose decrease during an insulin tolerance test was lower and HOMA insulin resistance indices were significantly higher in mutant mice, indicating the development of insulin resistance in mutant mice. The total islet volume, the volume density of beta-cells in the islets, and the total beta-cell volume of heterozygous male mutants was significantly reduced compared with wild-type mice. Electron microscopy of the beta-cells of male mutants showed virtually no secretory insulin granules, the endoplasmic reticulum was severely enlarged, and mitochondria appeared swollen. Thus, Munich Ins2(C95S) mutant mice are considered a valuable model to study the mechanisms of beta-cell dysfunction and death during the development of diabetes. [ABSTRACT FROM AUTHOR]

Purpose Systematic analysis of the ocular defects in a new mouse mutant carrying a Bmpr1b mutation. Methods The Bmpr1b mutants were analyzed by slit lamp, funduscopy, laser interference biometry, electroretinography, virtual drum, histology and in‐situ hybridization. Results The new Bmpr1b mutant is characterized by a T‐>G transversion in the splice donor site of exon 10. The mutants show irregular forelimb and hindlimb morphology, brachydactyly, irregular cartilage development and alterations in the reproductive system. The lens is clear, but in homozygous mutants, an enlarged optic disc was observed by funduscopy. The eyes are slightly larger, which is mainly due to an increased aqueous humor. Electroretinography demonstrated a more rapid decline of the b‐wave indicating a less efficient transmission of electric stimuli within the retina. Moreover, homozygous mutant mice show also almost no response to moving stripes as compared to the wild type mice. Histological analysis indicated dramatic changes in the optic nerve head. Analysis of the embryonic development of the eye showed that the expression area of Pax6 expands posterior, and concomitantly, Pax2 expression (which is regular at embryonic day 11.5) is repressed at embryonic days 15.5 and 17.5 at the optic nerve head. Conclusion The T‐G mutation in the splice donor site of exon 10 of the Bmpr1b gene leads to a recessive hypoplasia of the optic nerve head, which is mainly caused by repression of Pax2 expression in the late phase of embryogenesis. [ABSTRACT FROM AUTHOR]