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Genetics, Vol 130, 367-375, Copyright © 1992
INVESTIGATIONS |
Molecular Genetic Analysis of the mld(r) Mouse: A Spontaneous Revertant at the mld Locus Containing a Recombinant Myelin Basic Protein Gene
K. Ainger, E. Barbarese, L. Berman and J. H. Carson
Departments of Biochemistry, University of Connecticut Health Center, Farmington, Connecticut 06032
The mld mutation is a complex genetic lesion affecting the myelin basic protein (MBP) locus in the mouse. The mutation consists of a variety of DNA rearrangements including: tandem duplication of the MBP structural gene, partial inversion of the 3' end of the upstream gene copy, duplication of a region flanking the rearrangement junction in the upstream copy and insertion between the two gene copies of a segment of extraneous DNA not associated with the wild-type MBP locus. The net result of the mutation is a dysfunctional MBP locus. Homozygous mld/mld mice produce very little MBP and consequently very little myelin. The exhibit a clinical phenotype characteristic of hypomyelination (shaking, convulsions). We have discovered a revertant mld mouse which does not exhibit clinical symptoms of hypomyelination. Genetic analysis indicates that the reversion is allelic to mld. We have designated the revertant locus mld(r). Restriction analysis of mld(r) genomic DNA indicates that there is a single intact MBP gene. Analysis of various junction regions using the polymerase chain reaction indicates that the single MBP gene in mld(r) is derived by recombination from the 5' end of the upstream gene and the 3' end of the downstream gene. Studies on MBP expression in mld(r) mice indicate that the developmental regulation, level of expression and pattern of post-transcriptional processing of MBP gene products in mld(r) are similar to wild type. These results indicate that the recombinant MBP gene in mld(r) is fully functional. From this we infer that the MBP-deficient phenotype of the original mld mutant is attributable to the complex rearrangements in the upstream gene copy which render the locus dysfunctional. Elimination of the rearranged DNA in mld(r) restores function to the locus and ameliorates the mutant phenoptype.