Dominant-negative action of the jimpy mutation in mice complemented with an autosomal transgene for myelin proteolipid protein.

Abstract

Mutations in genes encoding membrane proteins have been associated with cell death of unknown cause from invertebrate development to human degenerative diseases. A point mutation in the gene for myelin proteolipid protein (PLP) underlies oligodendrocyte death and dysmyelination in jimpy mice, an accurate model for Pelizaeus-Merzbacher disease. To distinguish the loss of PLP function from other effects of the misfolded protein, we took advantage of the X chromosomal linkage of the gene and have complemented jimpy with a wild-type PLP transgene. In this artificial heterozygous situation, the jimpy mutation emerged as genetically dominant. At the cellular level oligodendrocytes showed little increase in survival although endogenous PLP gene and autosomal transgene were truly coexpressed. In surviving oligodendrocytes, wild-type PLP was functional and immunodetectable in myelin. Moreover, compacted myelin sheaths regained their normal periodicity. This strongly suggests that, despite the presence of functional wild-type PLP, misfolded jimpy PLP is by itself the primary cause of abnormal oligodendrocyte death.

• Authors: A M Schneider, I R Griffiths, C Readhead, K A Nave
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 92 Issue 10 Pg. 4447-51 (May 09 1995) ISSN: 0027-8424 [Print] United States
• PMID: 7538670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Myelin Proteins
• Myelin Proteolipid Protein
• RNA, Messenger

Topics

• Animals
• Base Sequence
• Brain (metabolism)
• DNA Primers
• Exons
• Gene Expression
• Genetic Complementation Test
• Genetic Linkage
• Heterozygote
• Homozygote
• Introns
• Mice
• Mice, Jimpy
• Mice, Transgenic
• Molecular Sequence Data
• Myelin Proteins (biosynthesis, genetics)
• Myelin Proteolipid Protein
• Point Mutation
• Polymerase Chain Reaction
• RNA, Messenger (biosynthesis)
• X Chromosome