ABSTRACT
Low blood sugar levels are a well-known cause of severe illness and often death in newborn humans, especially those that are small for age. Few of the causes of neonatal hypoglycemia are known, and many remain to be found. We describe a novel mouse mutant, skijumper (skimp), in which pups, despite feeding well, have low levels of glucose and develop opisthotonos, followed by death typically within a few days after birth. Genetic mapping studies have localized the lesion to a approximately 1 cM interval on mouse Chromosome (Chr) 7 between D7Mit318 and D7Mit93. We have carried out extensive analysis to define the phenotype and its likely cause. In addition to low blood glucose, affected skijumper mice have lowglycogen and ketone levels. Mass spectrometric analysis of blood samples has excluded major defects in amino acid metabolism. Initial biochemical analyses suggested a defect in ketogenesis as one possible cause of this phenotype. However, measurements of levels and activities of carnitine, carnitine palmitoyl transferases, and other enzymes involved in ketogenesis, along with studies of mitochondrial structure and function, did not demonstrate significant differences between skijumper, unaffected littermates, and control wild-type mice. These results indicate that abnormal enzyme activity in known pathways does not appear to be the primary biochemical lesion in skijumper. The skijumper may be a new valuable model for studying and understanding one type of neonatal morbidity and death.
Subject(s)
Chromosomes, Mammalian/genetics , Hypoglycemia/genetics , Mutation/genetics , 3-Hydroxybutyric Acid/blood , Animals , Animals, Newborn , Blood Glucose/analysis , Chromosome Mapping , Crosses, Genetic , Female , Glycogen/blood , Hypoglycemia/blood , Hypoglycemia/congenital , Hypoglycemia/pathology , Inheritance Patterns , Liver/metabolism , Liver/pathology , Liver/ultrastructure , Male , Mice , Mice, Mutant Strains , Microscopy, Electron , Mutation/radiation effects , Phenotype , Polymerase Chain ReactionABSTRACT
A variety of loci with interesting patterns of regulation such as imprinted expression, and critical functions such as involvement in tumour necrosis factor pathways, map to a distal portion of mouse chromosome 12. This region also contains disease related loci including the 'Legs at odd angles' mutation (Loa) that we are pursuing in a positional cloning project. To further define the region and prepare for comparative sequencing projects, we have produced genetic, radiation hybrid, physical and transcript maps of the region, with probes providing anchors between the maps. We show a summary of 95 markers and 91 genomic clones that has enabled us to identify 18 transcripts including new genes and candidates for Loa which will help in future studies of gene context and regulation.
