A goal of our site is to "determine the functional effects of polymorphisms on protein function and response to drugs in vitro" with respect to pharmacologic therapy and arrhythmia risk. The contribution of my laboratory to the PGRN PAT is focused in this area. Physiologic and biophysical studies have identified genes whose protein products are candidate modulators of the action of drugs used in arrhythmia treatment.

Our studies have focused on developing a mechanistic understanding of how new genes and gene sequence variants linked to defined populations alter protein function, a necessary step in developing a full understanding of how polymorphisms relate clinically to outcomes of drug therapy. To place our findings in a physiologic context, variant cDNAs are constructed, expressed, and their function and response to drug exposure are analyzed.

An example of our recent work involves studies in the cardiac sodium channel gene, SCN5A, where a number of rare mutations have been associated with life-threatening cardiac arrhythmias, including the long QT syndrome, the Brugada syndrome, and more recently cardiac conduction disease, a source of disability in millions of people worldwide. We have recently identified the role of an SCN5A polymorphism (H558R), occurring in 25% of the population, in modulating the functional effects of an SCN5A mutation (T512I) on a complex allele that evokes a cardiac conduction defect (The Journal of Clinical Investigation. 111:341-346, 2003). Our data are the first to suggest a direct functional association between a polymorphism and an arrhythmia-linked mutation in the same gene.

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