Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita

Andrea I. McClatchey, Peter Van den Bergh, Margaret A. Pericak-Vance, Wendy Raskind, Christine Verellen, Diane McKenna-Yasek, Keshav Rao, Jonathan L. Haines, Thomas Bird, Robert H. Brown, James F. Gusella

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187 Scopus citations

Abstract

Paramyotonia congenita (PMC), a dominant disorder featuring cold-induced myotonia (muscle stiffness), has recently been genetically linked to a candidate gene, the skeletal muscle sodium channel gene SCN4A. We have now established that SCN4A is the disease gene in PMC by identifying two different single-base coding sequence alterations in PMC families. Both mutations affect highly conserved residues in the III-IV cytoplasmic loop, a portion of the sodium channel thought to pivot in response to membrane depolarization, thereby blocking and inactivating the channel. Abnormal function of this cytoplasmic loop therefore appears to produce the Na+ current abnormality and the unique temperature-sensitive clinical phenotype in this disorder.

Original languageEnglish (US)
Pages (from-to)769-774
Number of pages6
JournalCell
Volume68
Issue number4
DOIs
StatePublished - Feb 21 1992
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    McClatchey, A. I., Van den Bergh, P., Pericak-Vance, M. A., Raskind, W., Verellen, C., McKenna-Yasek, D., Rao, K., Haines, J. L., Bird, T., Brown, R. H., & Gusella, J. F. (1992). Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita. Cell, 68(4), 769-774. https://doi.org/10.1016/0092-8674(92)90151-2