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Physiol. Genomics (November 26, 2002). doi:10.1152/physiolgenomics.00117.2002
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Articles in PresS, published online ahead of print November 26, 2002
Physiol Genomics, 10.1152/physiolgenomics.00117.2002
Submitted on September 11, 2002
Accepted on November 26, 2002

A COMMON HUMAN SCN5A POLYMORPHISM MODIFIES EXPRESSION OF AN ARRHYTHMIA CAUSING MUTATION

Bin Ye1, Carmen R Valdivia1, Michael J Ackerman2, and Jonathan C Makielski1*

1 Medicine, University of Wisconsin, Madison, Wisconsin, USA
2 Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA

* To whom correspondence should be addressed. E-mail: jcm{at}medicine.wisc.edu.

SCN5A encodes the {alpha} subunit of the ion channel that carries Na current in human heart. From a human cardiac cDNA library we recloned SCN5A. The new clone hH1b differed from existing clones hH1 in 4 and from hH1a in 3 positions. The common polymorphism H558R was uniquely present in hH1b. Voltage clamp study showed minor but potentially important kinetic differences between hH1b and the other clones. More dramatically, when the LQT3 mutation M1766L was introduced into the different clones Na current was markedly reduced in the hH1 and hH1a backgrounds, whereas in hH1b the Na current was not reduced. Immunocytochemistry experiments showed a trafficking defect for M1766L Na channels in hH1 and hH1a, but not in hH1b. The double mutation M1766L/H558R in the hH1a background restored normal trafficking and current including persistent late current, suggesting the disease phenotype was the result of a "double hit" that included the common polymorphism, H558R. These results show that the choice of background clone must be carefully considered in mutagenesis studies. This also represents an example of intragenic complementation, the first for such a large protein.




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