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© 1994 Oxford University Press

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Pathophysiology of sodium channelopathies: correlation of normal/mutant mRNA ratios with clinical phenotype in dominantly inherited periodic paralysis

Jianhua Zhou, Sharon J. Spier1, Jill Beech2 and Eric P. Hoffman*

Departments of Molecular Genetics and Biochemistry, Human Genetics, and Pediatrics, University of Pittsburgh School of Medicine Pittsburgh PA 15261 1Department of Medicine, School of Veterinary Medicine, University of California at Davis Davis, CA 95616 2New Bolton Center, School of Veterinary Medicine, University of Pennsylvania Kennett Square, PA 19348-1692, USA

*To whom correspondence should be addressed at: BST W1211, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA

Received April 26, 1994; Revised June 27, 1994; Accepted June 27, 1994

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.


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