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Dissertation
The effects of ryanodine receptor mutations on sodium channel transcription: implications for malignant hyperthermia
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Apr 1999
DOI:
https://doi.org/10.17918/00007461
Abstract
Malignant hyperthermia (MH) is a genetic, anesthesia-induced rhabdomyolytic disorder of skeletal muscle. A mutation in the ryanodine receptor (RYR1) has been shown to cause all known cases of MH in swine. To date, nineteen mutations in the RYR1 have been associate with human MH. A mutation in the dihydropyridine receptor (DHPR) has been recently identified in one MH family. The objective of these experiments is to further clarify the roles of three key proteins of excitation-contraction coupling in skeletal muscle, the RYR1, DHPR, and Na + channel, in the pathophysiology of MH. The central hypothesis is that MH mutations lead to altered expression of sodium channel isoforms, specifically down-regulation of SkM2. It is further hypothesized that the changes observed with the specific RYR1 mutations are similar to what is observed in vivo in a population of heterogenotic subjects. In order to test this hypothesis, three specific aims were pursued. The first aim focused on screening DNA from a large North American population for the presence of a RYR1 MH mutation, Gly341Arg. The North American population was also screened for the DHPR MH mutation Arg1086His. The second aim, the main thrust of this work, was to characterize sodium channel transcript levels in an isolated system in which a known MH mutation is the only variable. In the third aim, sodium channel isoform transcript levels were measured in a different model of rhabdomyolysis (horses with chronic intermittent rhabdomyolysis [CIR]) to compare with those in MH. The results demonstrate that the RYR1 Gly341Arg mutation is not present in the large MH population described here and the DHPR Arg1086His mutation was present in approximately 1% of our MH population. Results from the second aim conclusively demonstrate that the SkM2 isoform of the sodium channel is significantly down-regulated secondarily in response to transfection with mutant forms of the RYR1. And in aim 3, it was determined that the SkM1 isoform of the sodium channel may have a role in the pathophysiology of the rhabdomyolytic disorder CIR. In summary, currently identified MH mutations account for a very small percentage of MH in our population. Therefore, the population frequency estimates for known human MH mutations are inconsistent with the data obtained in this North American population. SkM2 is the first transcript that has been shown to be downregulated by a specific MH mutation. This is the first clear demonstration of this cause-effect relationship phenomenon and establishes a model system in which to examine the previously reported association of SkM2 down-regulation with muscle from MH susceptible humans. The results of this work suggest that the many factors that regulate the expression of MH and this effect may contribute to the pathophysiology of the disease. (Abstract shortened by UMI.).
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Details
- Title
- The effects of ryanodine receptor mutations on sodium channel transcription
- Creators
- Sherri L. Stewart
- Contributors
- Jeffrey E. Fletcher (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- x, 100, 18, 3 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888876104721