Mice homozygous for the megencephaly spontaneous mutation (Kcna1mceph) are characterized by a 25% increase in brain size in the first 8 months of life. This defect can be distinguished from macrocephaly, an enlarged head, which usually occurs as a consequence of congenital hydrocephalus. By 3-4 weeks of age, mice homozygous for the mceph mutation have a subtle shakiness in their gate and by 4-6 weeks are found to sit on their haunches using their tails as support with their forelimbs held loosely in front of them. They maintain this posture for a period ranging from 30 seconds to several minutes before returning to normal. They have lower overall body weights than their wildtype littermates and are hypersensitive to sharp sounds. Electroencephalogram readings for homozygotes are normal. Neither male nor female mutants breed, but ovarian transplant from homozygous donors is successful for colony maintenance. Homozygotes have an increased brain mass that is evident by one to two months of age and increases at least until 10 weeks of age, possibly longer. Hypertrophic astrocytes in the hippocampus were the only lesion detected by electron microscopy. This increase in brain mass does not appear to result from edema, hydrocephalus, or an increase in size restricted to any specific area of the brain. The ventricles were not found to be dilated, and no apparent increase in myelin was found. Two month old homozygotes did not show BrdU uptake in brain tissue, and the protein:DNA ration was normal. Thus, mceph appears to cause overall hypertrophy of cells in the brain rather than hyperplasia. Brains from homozygotes have only 13.8% fat while wild type have 15.6% fat.
In several evolutionarily associated regions of the brain, Petersson et al. found co-localized increases in mRNA levels for transforming growth factor beta 1, and insulin-like growth factor binding proteins 2, 4, 5, and 6 with decreases in mRNA levels for Insulin-like growth factor binding protein 5. These imbalances were found in the cerebral cortex, hippocampus, amygdala, and piriform/entorhinal cortex of homozygotes. They also reported a decreased transcript level in the corpus callosum for proteolipid protein of myelin. Immunohistochemistry and in situ hybridization also revealed changes in the expression levels of enkephalin, galanin, neuropeptide Y, and cholecystokinin in specific regions of the hippocampal formation and in ventral cortices. (Petersson et al., 1999; Peterson et al., 2000.)
Megencephaly occurs in several acquired and inherited human diseases including Sotos syndrome, Robinow syndrome, Canavan's disease, and Alexander disease.
The mceph mutation arose spontaneously on the BALB/cByJ inbred background at The Jackson Laboratory in 1983. It was maintained primarily via a backcross-intercross breeding scheme in which the backcross used a BALB/cByJ male bred to a host female transplanted with ovarian tissue from a homozygous female. Attempts to freeze embryos on the pure BALB/cByJ background were not adequately successful. Thus, this strain was frozen in 1995 by breeding C57BL/6J females to heterozygous BALB/cByJ-mceph males. Thus the embryos are heterozygous or wildtype F1.
|Allele Synonym(s)||Kv1.1mceph; mceph|
|Gene Symbol and Name||Kcna1, potassium voltage-gated channel, shaker-related subfamily, member 1|
|Strain of Origin||BALB/cByJ|
|Molecular Note||An 11 bp deletion occurs in this mutant, either between bp 2124 and 2134 or between 2129 and 2139. This deletion causes a frame shift which creates a premature stop codon. The resulting protein is 230 amino acids in length as opposed to 495 amino acids for a normal protein. The cytosolic N-terminal, first transmembrane segment and extracellular loop of the protein are preserved.|