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

Jianhua Zhou, Sharon Spier, Jill Beech, Eric P. Hoffman

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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 (> 50000) 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.

Original languageEnglish (US)
Pages (from-to)1599-1603
Number of pages5
JournalHuman Molecular Genetics
Issue number9
StatePublished - Sep 1994

ASJC Scopus subject areas

  • Genetics
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Public Health, Environmental and Occupational Health
  • Molecular Biology
  • Genetics(clinical)


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