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Our laboratory has been using spontaneous mutations in rodents as genetic tools to understand functions of genes in health and disease. We have described a naturally occurring mutation (Nuc1) in the Sprague-Dawley rat with a novel and unusual eye phenotype. More recently we discovered that the Nuc1 allele results from mutation of the βA3/A1-crystallin gene, which in the neural retina is expressed only in astrocytes.

We have demonstrated striking structural abnormalities in Nuc1 astrocyte with profound effects on the organization of intermediate filaments. Our data implicate βA3/A1-crystallin as an important regulatory factor mediating normal astrocyte function during development of the CNS.

A second severe de novo mutation arose spontaneously in our Nuc1 colony. The mutation has been named frogleg because of the "frog-like" gait resulting from hind limb hypertonicity with hyperextension and dorsal rotation. These mutant animals exhibit a dramatic reduction in brain weight. In addition, brain ventricles are much larger than normal. Schwann cells in the sciatic nerves of frogleg rats are morphologically abnormal and the sciatic nerve compound muscle action potential is also significantly reduced. The hind limb musculature reveals denervation atrophy. Neurologically based pathologies, including motor neuropathies, are among the most significant and debilitating human diseases. Most such diseases are poorly understood from a mechanistic point of view, resulting in very limited therapeutic options. Animal model systems such as Nuc1 and frogleg can be invaluable in the study of such diseases.

The Glia Research Laboratory Staff. Learn More