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CAP2 in cardiac conduction, sudden cardiac death and eye development.

Field J, Ye DZ, Shinde M, Liu F, Schillinger KJ, Lu M, Wang T, Skettini M, Xiong Y, Brice AK, Chung DC, Patel VV - Sci Rep (2015)

Bottom Line: One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics.To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes.We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.

ABSTRACT
Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease.

No MeSH data available.


Related in: MedlinePlus

Effects of CAP2 knockout on animal growth.(a) Growth of male pups; (b) Growth of female pups; (c) Adult male body weight. Error bars ± S.E.M.
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f2: Effects of CAP2 knockout on animal growth.(a) Growth of male pups; (b) Growth of female pups; (c) Adult male body weight. Error bars ± S.E.M.

Mentions: We also monitored the weight of male and female cap2−/cap2− mutants, heterozygotes and littermate controls for three weeks (Fig. 2). Both male and female cap2−/cap2− had similar weights as other groups at birth, but they grew at significantly slower rates than heterozygotes and wild-type controls. For male mutants, this trend was even more pronounced and their weight was significantly lower as early as postnatal day 3. By postnatal day 21, both male and female mutants were still smaller than age-matched heterozygotes and wild-type controls. To address if the stunted growth had a metabolic cause we performed Whole Body Dual X-Ray Absorptiometry (DEXA), but did not observe differences (Supplementary Figures S1a and S1c). Mutants were weaker in grip strength assays (Supplementary Figure S1b), but the differences were probably a reflection of their smaller size. We did not observe any abnormalities in isolated EDL muscles when analyzed by electron microscopy (data not shown). The mutants were normal for glucose (Supplementary Figure S1d) and the utilization of fuels by the respiration exchange ratio (RER) (Supplementary Figure S2).


CAP2 in cardiac conduction, sudden cardiac death and eye development.

Field J, Ye DZ, Shinde M, Liu F, Schillinger KJ, Lu M, Wang T, Skettini M, Xiong Y, Brice AK, Chung DC, Patel VV - Sci Rep (2015)

Effects of CAP2 knockout on animal growth.(a) Growth of male pups; (b) Growth of female pups; (c) Adult male body weight. Error bars ± S.E.M.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663486&req=5

f2: Effects of CAP2 knockout on animal growth.(a) Growth of male pups; (b) Growth of female pups; (c) Adult male body weight. Error bars ± S.E.M.
Mentions: We also monitored the weight of male and female cap2−/cap2− mutants, heterozygotes and littermate controls for three weeks (Fig. 2). Both male and female cap2−/cap2− had similar weights as other groups at birth, but they grew at significantly slower rates than heterozygotes and wild-type controls. For male mutants, this trend was even more pronounced and their weight was significantly lower as early as postnatal day 3. By postnatal day 21, both male and female mutants were still smaller than age-matched heterozygotes and wild-type controls. To address if the stunted growth had a metabolic cause we performed Whole Body Dual X-Ray Absorptiometry (DEXA), but did not observe differences (Supplementary Figures S1a and S1c). Mutants were weaker in grip strength assays (Supplementary Figure S1b), but the differences were probably a reflection of their smaller size. We did not observe any abnormalities in isolated EDL muscles when analyzed by electron microscopy (data not shown). The mutants were normal for glucose (Supplementary Figure S1d) and the utilization of fuels by the respiration exchange ratio (RER) (Supplementary Figure S2).

Bottom Line: One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics.To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes.We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.

ABSTRACT
Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease.

No MeSH data available.


Related in: MedlinePlus