Using human iPS cells and cardiomyocytes — or heart muscle cells — with recombinant calmodulin proteins, the team studied catecholaminergic polymorphic ventricular tachycardia — or CPVT, a rare and life-threatening genetic condition.
“Two patients carrying this variant in the CALM2 gene, a member of the calmodulin gene family, showed not only arrhythmia but also neurological abnormalities, suggesting its variable pathogenicity,” notes lead author Takeru Makiyama of Kyoto University.
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Abnormalities in CALM genes
In humans, CaM is encoded by three different CALM genes that produce the same amino acid sequenceall three are expressed in the heart.
Makiyama’s team was able to reproduce the severe arrhythmia in patient-derived iPS cell models of exercise-induced CPVT with calmodulin mutations.
Using recombinant proteins, the molecular mechanism was deduced by biochemical methods. CPVT-associated CaMs were found to bind dominantly to the cardiac ryanodine receptor, a major calcium release channel in cardiomyocytes.
“When we analyzed several patient-specific iPSC-derived cardiomyocyte models, we were impressed that they exhibited varying degrees of arrhythmogenicity,” adds Makiyama, referring to the study’s use of induced pluripotent stem cells.
“Future evaluation of the efficacy of antiarrhythmic drugs in iPS cell models will help to develop precision medicine for CaM-related CPVT patients.”
Source: Eurekalert
