Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Elsevier Science full text link Elsevier Science Free PMC article
Full text links

Actions

Comparative Study
.2008 Aug;45(2):281-8.
doi: 10.1016/j.yjmcc.2008.05.003. Epub 2008 May 11.

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C

Affiliations
Comparative Study

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C

Andrew P Landstrom et al. J Mol Cell Cardiol.2008 Aug.

Abstract

Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes, and has been associated with mutations in most sarcomeric proteins (tropomyosin, troponin T and I, and actin, etc.). Many of these mutations appear to affect the functional properties of cardiac troponin C (cTnC), i.e., by increasing the Ca(2+)-sensitivity of contraction, a hallmark of HCM, yet surprisingly, prior to this report, cTnC had not been classified as a HCM-susceptibility gene. In this study, we show that mutations occurring in the human cTnC (HcTnC) gene (TNNC1) have the same prevalence (~0.4%) as well established HCM-susceptibility genes that encode other sarcomeric proteins. Comprehensive open reading frame/splice site mutation analysis of TNNC1 performed on 1025 unrelated HCM patients enrolled over the last 10 years revealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. Functional studies with these recombinant HcTnC HCM mutations showed increased Ca(2+) sensitivity of force development (A8V, C84Y and D145E) and force recovery (A8V and D145E). These results are consistent with the HCM functional phenotypes seen with other sarcomeric-HCM mutations (E134D showed no changes in these parameters). This is the largest cohort analysis of TNNC1 in HCM that details the discovery of at least three novel HCM-associated mutations and more strongly links TNNC1 to HCM along with functional evidence that supports a central role for its involvement in the disease. This study may help to further define TNNC1 as an HCM-susceptibility gene, a classification that has already been established for the other members of the troponin complex.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Mapping and modeling of HCM-susceptibility mutations inTNNC1-encoded cardiac troponin C (HcTnC)
A) The gene and protein linear topology of HcTnC, including exon, splice junction, functional domains, and calcium binding site locations. The location of each of the four mutations is noted respectively.B) N-terminus (left) depicting the location of A8V and C84Y mutations in relationship to the Ca2+ binding sites and HcTnC helices. Ca2+ binding site I is defunct and Ca2+ binding site II shows Ca2+ bound (green sphere); N-helix (blue), A-helix (pink), B-helix (green), C-helix (orange), and D-helix (red). The Ala8 is located in the first helix of TnC in the beginning of the flexible linker connecting the two domains. C-terminus (right) depicting the location of E134D and D145E mutations in relationship to Ca2+ binding sites and helices. Ca2+ binding site III and IV pictured with Ca2+ bound (green spheres); E-helix (blue), F-helix (pink), G-helix (orange), H-helix (red). Glu134 is located in the G-helix between Ca2+ binding sites III and IV and Asp145 is situated at the Z position of Ca2+ coordinating residues of site IV.
Figure 2
Figure 2. Sequence conservation
The identified mutations inTNNC1 localize to residues completely conserved across all species queried.
Figure 3
Figure 3. The Ca2+ dependence of force development and maximal relative force in reconstituted muscle fibers
A) Ca2+ dependence of force development in (●) WT, (▲) A8V, (♦) C84Y, (▼) E134D, and (■) D145E.B) Relative force recovery measured after HcTnC reconstitution normalized to the initial force. Data in each experiment are the average of 7–9 experiments and are expressed as mean ± S.E. in Table 3.
See this image and copyright information in PMC

References

    1. Maron BJ, Roberts WC, McAllister HA, Rosing DR, Epstein SE. Sudden death in young athletes. Circulation. 1980;62:218–229. - PubMed
    1. Maron BJ, Epstein SE, Roberts WC. Causes of sudden death in competitive athletes. J Am Coll Cardiol. 1986;7:204–214. - PubMed
    1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. 1995;92:785–789. - PubMed
    1. Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, et al. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994;77:701–712. - PubMed
    1. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full text links
Elsevier Science full text link Elsevier Science Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp