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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

Eye infections and microphthalmia in knockout mice.(a) Pupil diameter in cap2−/cap2− and cap2+/cap2+ mice. Error bars ± S.D. (b) Examples of eye infections seen in cap2−/cap2− mice. Photos by DCC. (c) CAP2 expression in lens, retina, cornea and retinal pigment epithelium (RPE) was determined by qPCR.
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f3: Eye infections and microphthalmia in knockout mice.(a) Pupil diameter in cap2−/cap2− and cap2+/cap2+ mice. Error bars ± S.D. (b) Examples of eye infections seen in cap2−/cap2− mice. Photos by DCC. (c) CAP2 expression in lens, retina, cornea and retinal pigment epithelium (RPE) was determined by qPCR.

Mentions: We found that knockouts were prone to eye inflammation and infections, which were observed in almost all males and about half of the females. Infections typically appeared at about 6 weeks of age and were more common in the right eye than the left eye. To address if infections were associated with vision problems, we performed electroretinography and pupillometry but did not find any significant differences from normal mice (data not shown). However, the diameters of pupils in male mutants were significantly decreased, suggesting an underlying eye development problem such as microphthalmia (Fig. 3a,b). Expression was detected in several regions of the eye and was highest in the retina and lens (Fig. 3c)35.


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)

Eye infections and microphthalmia in knockout mice.(a) Pupil diameter in cap2−/cap2− and cap2+/cap2+ mice. Error bars ± S.D. (b) Examples of eye infections seen in cap2−/cap2− mice. Photos by DCC. (c) CAP2 expression in lens, retina, cornea and retinal pigment epithelium (RPE) was determined by qPCR.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Eye infections and microphthalmia in knockout mice.(a) Pupil diameter in cap2−/cap2− and cap2+/cap2+ mice. Error bars ± S.D. (b) Examples of eye infections seen in cap2−/cap2− mice. Photos by DCC. (c) CAP2 expression in lens, retina, cornea and retinal pigment epithelium (RPE) was determined by qPCR.
Mentions: We found that knockouts were prone to eye inflammation and infections, which were observed in almost all males and about half of the females. Infections typically appeared at about 6 weeks of age and were more common in the right eye than the left eye. To address if infections were associated with vision problems, we performed electroretinography and pupillometry but did not find any significant differences from normal mice (data not shown). However, the diameters of pupils in male mutants were significantly decreased, suggesting an underlying eye development problem such as microphthalmia (Fig. 3a,b). Expression was detected in several regions of the eye and was highest in the retina and lens (Fig. 3c)35.

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