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Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Dijk, Sabine J. Van Dooijes, Dennis Remedios, Cristobal G. Dos Michels, Michelle Lamers, Jos M. J. Winegrad, Saul Schlossarek, Saskia Carrier, Lucie Cate, Folkert J. Ten Stienen, Ger J. M. Velden, Jolanda Van Der |
| Copyright Year | 2009 |
| Abstract | BACKGROUND Mutations in the MYBPC3 gene, encoding cardiac myosin-binding protein C (cMyBP-C), are a frequent cause of familial hypertrophic cardiomyopathy. In the present study, we investigated whether protein composition and function of the sarcomere are altered in a homogeneous familial hypertrophic cardiomyopathy patient group with frameshift mutations in MYBPC3 (MYBPC3(mut)). METHODS AND RESULTS Comparisons were made between cardiac samples from MYBPC3 mutant carriers (c.2373dupG, n=7; c.2864_2865delCT, n=4) and nonfailing donors (n=13). Western blots with the use of antibodies directed against cMyBP-C did not reveal truncated cMyBP-C in MYBPC3(mut). Protein expression of cMyBP-C was significantly reduced in MYBPC3(mut) by 33+/-5%. Cardiac MyBP-C phosphorylation in MYBPC3(mut) samples was similar to the values in donor samples, whereas the phosphorylation status of cardiac troponin I was reduced by 84+/-5%, indicating divergent phosphorylation of the 2 main contractile target proteins of the beta-adrenergic pathway. Force measurements in mechanically isolated Triton-permeabilized cardiomyocytes demonstrated a decrease in maximal force per cross-sectional area of the myocytes in MYBPC3(mut) (20.2+/-2.7 kN/m(2)) compared with donor (34.5+/-1.1 kN/m(2)). Moreover, Ca(2+) sensitivity was higher in MYBPC3(mut) (pCa(50)=5.62+/-0.04) than in donor (pCa(50)=5.54+/-0.02), consistent with reduced cardiac troponin I phosphorylation. Treatment with exogenous protein kinase A, to mimic beta-adrenergic stimulation, did not correct reduced maximal force but abolished the initial difference in Ca(2+) sensitivity between MYBPC3(mut) (pCa(50)=5.46+/-0.03) and donor (pCa(50)=5.48+/-0.02). CONCLUSIONS Frameshift MYBPC3 mutations cause haploinsufficiency, deranged phosphorylation of contractile proteins, and reduced maximal force-generating capacity of cardiomyocytes. The enhanced Ca(2+) sensitivity in MYBPC3(mut) is due to hypophosphorylation of troponin I secondary to mutation-induced dysfunction. |
| File Format | PDF HTM / HTML |
| DOI | 10.1161/CIRCULATIONAHA.108.838672 |
| PubMed reference number | 19273718 |
| Journal | Medline |
| Volume Number | 119 |
| Issue Number | 11 |
| Alternate Webpage(s) | http://circ.ahajournals.org/content/circulationaha/119/11/1473.full.pdf?download=true |
| Alternate Webpage(s) | http://dare.ubvu.vu.nl/bitstream/handle/1871/19215/chapter%205.pdf?isAllowed=y&sequence=5 |
| Alternate Webpage(s) | https://doi.org/10.1161/CIRCULATIONAHA.108.838672 |
| Journal | Circulation |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
