Researchers find missplicing Scn5a alters cardiac function
Missplicing genes using CRISPR
Using CRISPR technology, Cooper and his colleagues removed the gene segment containing the adult form of Scn5a. Consequently, the developing mice expressed fetal Scn5a when they became adults. The researchers then applied a variety of assays to measure alterations of the electrical conduction characteristics of the heart, including conduction velocity and susceptibility to arrhythmias.
“We found that the hearts of mice expressing the fetal form of Scn5a behaved differently than those of normal mice,” said first author Paul D. Pang, predoctoral fellow in Baylor’s Integrative Molecular and Biomedical Sciences Program. “Conduction velocity was slower and arrhythmias were more likely to occur in the hearts expressing fetal Scn5a.”
“We reproduced in mice the defects in heart function observed DM1 by making this change in alternative splicing, which supports the hypothesis that alternative splicing of Scn5a is a contributing factor in the cardiac problems associated with the disease and maybe also in arrhythmias linked to other conditions,” said Cooper, who also is the S. Donald Greenberg and R. Clarence and Irene H. Fulbright Professor and a member of the Dan L Duncan Comprehensive Cancer Center at Baylor.”
Next, the researchers plan to explore the possibility that changing the fetal form of Scn5a back to the adult form would help reinstate normal heart function.
Other contributors of this work include Katherina M. Alsina, Shuyi Cao, Amrita B. Koushik and Xander H.T. Wehrens, all at Baylor College of Medicine.
This study was funded by the National Institutes of Health (T32HL07676, F31HL140879, R01HL045565, R01AR045653, R01AR060733, R01HL089598, R01HL091947 and R01HL117641), the Muscular Dystrophy Foundation, the American Heart Association (13EIA14560061) and Saving Tiny Hearts Foundation.