Pathophysiology of sodium channelopathies: correlation of normal/mutant mRNA ratios with clinical phenotype in dominantly inherited periodic paralysis.
Abstract: It is often suggested that polygenic or environmental factors are responsible for clinical variability between patients with identical mutations. However, most dominant diseases are caused by a change-of-function alteration in the mutant allele's protein product. All patients are heterozygous and presumably express both mutant and normal proteins from the corresponding genes. Thus, a possible molecular mechanism for clinical variability could be the difference in relative levels of mutant vs. normal mRNA in different patients with the same mutation. To investigate this hypothesis, it is necessary to have access to a series of tissue biopsies from many patients with the same mutation causing a clinically variable dominant disease. Human hyperkalemic periodic paralysis (HyperPP) has been shown to be a clinically variable disorder caused by change-of-function mutations of the skeletal muscle sodium channel protein. We recently identified a large (> 50,000) pedigree of affected Quarter Horses sharing the same causative amino acid alteration of the muscle sodium channel protein. The horses like humans show substantial clinical variability. In this report, we developed a fluorescent reverse transcription-polymerase chain reaction assay which quantifies the relative levels of normal and mutant mRNA expression of the horse adult skeletal muscle sodium channel gene in affected Quarter Horses. We found that asymptomatic horses showed more normal sodium channel mRNA, while moderately affected horses showed more mutant mRNA. The ratios of mutant/normal mRNA between these two groups are statistically different, suggesting that severity of HyperPP Quarter Horses may indeed be correlated to the ratio of mutant and normal sodium channel gene expression in skeletal muscle.
Publication Date: 1994-09-01 PubMed ID: 7833917DOI: 10.1093/hmg/3.9.1599Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
- Research Support
- U.S. Gov't
- P.H.S.
Summary
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The research investigates the link between the severity of a genetic disorder in horses known as hyperkalemic periodic paralysis (HyperPP) and the ratio of normal to mutated gene expression. The researchers found that horses showing no symptoms had greater expression of normal genes while moderately affected horses had higher expression of the mutated gene.
Background of the Research
- The research is driven by the observation that often, the severity of disease symptoms can vary between patients carrying the same genetic mutation. The researchers propose that the variation in disease severity could be due to differences in the ratio of normal to mutated gene expression.
- The focus of this research is hyperkalemic periodic paralysis (HyperPP), a genetic disorder affecting both horses and humans, which causes intermittent muscle weakness and paralysis. This disorder is noted for its clinical variability, making it a fitting disease for this research.
- The researchers had identified a large pedigree of horses carrying the same genetic mutation causing HyperPP, providing a unique opportunity to assess the link between the ratio of normal to mutated gene expression and disease severity.
Methodology
- For this study, the team developed a method to measure the relative levels of normal and mutated mRNA (messenger Ribonucleic Acid) – essentially, the output of gene expression.
- This involved using a fluorescent reverse transcription-polymerase chain reaction assay – a technique which helps quantify the relative levels of gene expression.
Results and Interpretation
- The researchers found that the levels of normal and mutated mRNA varied depending on the severity of the disease. Horses with no symptoms of HyperPP were found to have higher levels of normal sodium channel mRNA, while those with moderate symptoms showed higher levels of the mutated version.
- The team found the ratios of mutated to normal mRNA between these two groups to be statistically different. They suggest the observed differences in disease severity may indeed be correlated to the ratio of normal and mutated sodium channel gene expression.
Implications
- These findings suggest that the severity of genetic disorders, such as hyperkalemic periodic paralysis, may be influenced by the ratio of normal to mutated gene expression.
- This could be significant in understanding the clinical variability seen in many diseases and could potentially inform future therapeutic approaches by manipulating the ratio of normal/mutant mRNA to reduce disease severity.
Cite This Article
APA
Zhou J, Spier SJ, Beech J, Hoffman EP.
(1994).
Pathophysiology of sodium channelopathies: correlation of normal/mutant mRNA ratios with clinical phenotype in dominantly inherited periodic paralysis.
Hum Mol Genet, 3(9), 1599-1603.
https://doi.org/10.1093/hmg/3.9.1599 Publication
Researcher Affiliations
- Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, PA 15261.
MeSH Terms
- Animals
- Base Sequence
- DNA / genetics
- Genes, Dominant
- Heterozygote
- Homozygote
- Horse Diseases / genetics
- Horse Diseases / physiopathology
- Horses
- Molecular Sequence Data
- Mutation
- Paralyses, Familial Periodic / genetics
- Paralyses, Familial Periodic / physiopathology
- Paralyses, Familial Periodic / veterinary
- Phenotype
- Polymerase Chain Reaction
- RNA, Messenger / genetics
- RNA, Messenger / metabolism
- Sodium Channels / genetics
- Sodium Channels / physiology
Grant Funding
- AR41025 / NIAMS NIH HHS
Citations
This article has been cited 6 times.- Cannon SC. Channelopathies of skeletal muscle excitability. Compr Physiol 2015 Apr;5(2):761-90.
- Tripathi S, Schultz I, Becker E, Montag J, Borchert B, Francino A, Navarro-Lopez F, Perrot A, Özcelik C, Osterziel KJ, McKenna WJ, Brenner B, Kraft T. Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy. Basic Res Cardiol 2011 Nov;106(6):1041-55.
- Jurkat-Rott K, Lehmann-Horn F. Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis. Neurotherapeutics 2007 Apr;4(2):216-24.
- Rhodes TH, Vanoye CG, Ohmori I, Ogiwara I, Yamakawa K, George AL Jr. Sodium channel dysfunction in intractable childhood epilepsy with generalized tonic-clonic seizures. J Physiol 2005 Dec 1;569(Pt 2):433-45.
- Featherstone DE, Fujimoto E, Ruben PC. A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita. J Physiol 1998 Feb 1;506 ( Pt 3)(Pt 3):627-38.
- Hall DH, Gu G, García-Añoveros J, Gong L, Chalfie M, Driscoll M. Neuropathology of degenerative cell death in Caenorhabditis elegans. J Neurosci 1997 Feb 1;17(3):1033-45.
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