Related Experiment Videos
Overexpression of DM20 messenger RNA in two brothers with Pelizaeus-Merzbacher disease
P Carango1, V L Funanage, R E Quirós
1Department of Medical Cell Biology, Alfred L. duPont Institute, Wilmington, DE 19899, USA.
Abstract:
Pelizaeus-Merzbacher disease is a rare, sex-linked recessive, dysmyelinating disease of the central nervous system that has been associated with mutations in the myelin proteolipid protein (PLP) gene. Only 25% of patients studied with Pelizaeus-Merzbacher disease have exonic mutations in this gene, the underlying cause of the disease in the remaining patients is unknown. The PLP gene encodes two major alternatively spliced transcripts called PLP and DM20. PLP messenger RNA is specifically expressed in central nervous system tissue, whereas DM20 messenger RNA is found in central nervous system, cardiac, and other tissues. We studied cultured skin fibroblasts from 2 brothers with Pelizaeus-Merzbacher disease who exhibited no detectable exonic mutation of the PLP gene. Examination of RNA from these cells showed that the level of DM20 messenger RNA is elevated sixfold relative to male control skin fibroblasts. An unrelated female carrier, also with no detectable exonic mutation, showed a threefold increase in DM20 messenger RNA in cultured skin fibroblasts. Our findings suggest that in some patients, Pelizaeus-Merzbacher disease is caused by overexpression of PLP gene transcripts, and that in these families a 50% increase of DM20 messenger RNA in females, relative to the increase in affected males, can identify a female carrier.
Insights
Pelizaeus-Merzbacher disease may stem from increased myelin proteolipid protein (PLP) gene transcripts. Elevated DM20 messenger RNA levels in fibroblasts suggest a new diagnostic marker for carriers.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Pelizaeus-Merzbacher disease (PMD) is a rare, sex-linked recessive, dysmyelinating disorder of the central nervous system.
- Mutations in the myelin proteolipid protein (PLP) gene are linked to PMD, but only account for 25% of cases, leaving the cause unknown in most patients.
- The PLP gene produces two transcripts: PLP and DM20, with differing tissue expression.
Purpose of the Study:
- To investigate the underlying cause of Pelizaeus-Merzbacher disease in patients lacking detectable exonic PLP gene mutations.
- To determine if altered expression levels of PLP gene transcripts contribute to the disease pathology.
- To identify potential carrier detection methods for families affected by PMD.
Main Methods:
- Cultured skin fibroblasts were obtained from two brothers with Pelizaeus-Merzbacher disease and no identified exonic PLP mutations.
- RNA was extracted from these fibroblasts and analyzed for transcript levels.
- Fibroblast cultures from an unrelated female carrier without exonic mutations were also analyzed.
Main Results:
- Fibroblasts from affected brothers showed a sixfold increase in DM20 messenger RNA compared to male controls.
- An unrelated female carrier exhibited a threefold increase in DM20 messenger RNA.
- These findings indicate elevated DM20 messenger RNA levels in individuals with PMD and carriers.
Conclusions:
- Overexpression of PLP gene transcripts, specifically DM20 messenger RNA, is a potential cause of Pelizaeus-Merzbacher disease in some patients.
- Increased DM20 messenger RNA in female carriers may serve as a diagnostic indicator.
- This study highlights a novel mechanism contributing to PMD pathogenesis and carrier identification.