Off tempo pg. 3
Rare diseases offer insight
Genetic screening can be done at the single gene or genome-wide level, or somewhere in between. The Leducq-funded investigators will take the middle road, looking for “places in the genes we know and love, so-called candidate genes, where variation might explain susceptibility to arrhythmias and sudden death,” Roden says.
Ion channels control the flow of electrically-charged ions acoss the cell membrane and thus can affect heart rhythm. Red and green figures show closed and open channels. The yellow figure shows a mutation that inhibits ion flow.
In 1995, Mark Keating, M.D., and colleagues at the University of Utah reported that mutations in two ion channel genes—one encoding a sodium channel, the other a potassium channel—cause congenital long QT syndrome. This disorder, named for the longer than normal time between two points—Q and T—on the electrocardiogram, affects about one in 1000 individuals in the United States and can cause a potentially fatal arrhythmia called torsades de pointes. Over the last decade, hundreds of distinct mutations that cause long QT syndrome have been identified in 11 different genes, almost all of them encoding ion channels in the heart.
Likewise, other rare inherited arrhythmias and heart muscle diseases like hypertrophic cardiomyopathy have been linked to mutations in ion channels, calcium-regulating proteins, and components of the muscle cell’s contractile apparatus.
The rare cardiac diseases were once only interesting for purposes of “hospital roundsmanship,” Roden says, but “their importance now goes well beyond that.” They have revealed that the heart is composed of highly interconnected and interdependent systems, and that a defect in just one component of the system can cause a dramatic phenotype.
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