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.
ASJC Scopus subject areas
- Clinical Neurology