CLINICAL STUDY: HYPERTROPHIC CARDIOMYOPATHY
Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy
Roselie J. Jongbloed* ,*,
Carlo L. Marcelis, MD ,
Pieter A. Doevendans, MD, PhD ,
Judith M. Schmeitz-Mulkens, MSc ,
Willem G. Van Dockum, MD ||,
Joep P. Geraedts, PhD* and
Hubert J. Smeets, PhD*
* Department of Genetics and Cell Biology, University of Maastricht, Maastricht, the Netherlands
Department of Clinical Genetics, Academic Hospital Maastricht, Maastricht, the Netherlands
Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, the Netherlands
Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, the Netherlands
|| Department of Cardiology, VU Medical Center Amsterdam, Amsterdam, the Netherlands
Manuscript received May 29, 2002;
revised manuscript received October 25, 2002,
accepted November 18, 2002.
* Reprint requests and correspondence: Roselie J. E. Jongbloed, Department of Genetics and Cell Biology, University Maastricht, Joseph Bechlaan 113, 6229 GR Maastricht, the Netherlands. roselie.jongbloed{at}gen.unimaas.nl
OBJECTIVES: This study was initiated to identify the disease-causing genetic defect in a family with hypertrophic cardiomyopathy (HCM) and high incidence of sudden death.
BACKGROUND: Familial hypertropic cardiomyopathy (FHC) is an autosomal dominant transmitted disorder that is genetically and clinically heterogeneous. Mutations in 11 genes have been associated with the pathogenesis of the disease.
METHODS: We studied a large FHC family, first by linkage analysis, to identify the gene involved, and subsequently screened the gene, encoding alpha-tropomyosin (TPM1), for mutations by using single-strand conformation polymorphism and sequencing analysis.
RESULTS: Twelve family members presented clinical features of HCM, five of whom died at young age, while others had only mild clinical features. Marker analysis showed linkage for the TPM1 gene on chromosome 15q22 (maximal logarithm of the odds score is 5.16, = 0); subsequently, a novel missense mutation (Glu62Gln) was identified.
CONCLUSIONS: The novel mutation identified in TPM1 is associated with the clinical features of cardiac hypertrophy in all but one genetically affected member of this large family. The clinical data suggest a malignant phenotype at young age with a variable clinical manifestation and penetrance at older age. The Glu62Gln mutation is the sixth TPM1 mutation identified as the cause of FHC, indicating that mutations in this gene are very rare. This is the first reported amino acid substitution at the f-position within the coiled-coil structure of the tropomyosin protein.
|
Abbreviations and Acronyms
| | cM | | centiMorgan | | DCM | | dilated cardiomyopathy | | FHC | | familial hypertrophic cardiomyopathy | | HCM | | hypertrophic cardiomyopathy | | LV | | left ventricular | | MYBPC | | myosin binding protein C | | MYH7 | | beta-cardiac myosin heavy chain | | TNNT2 | | troponin T | | TPM1 | | alpha-tropomyosin |
|
This article has been cited by other articles:

|
 |

|
 |
 
J. Ochala, M. Li, M. Ohlsson, A. Oldfors, and L. Larsson
Defective regulation of contractile function in muscle fibres carrying an E41K {beta}-tropomyosin mutation
J. Physiol.,
June 15, 2008;
586(12):
2993 - 3004.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
G. Jagatheesan, S. Rajan, N. Petrashevskaya, A. Schwartz, G. Boivin, G. M. Arteaga, R. John Solaro, S. B. Liggett, and D. F. Wieczorek
Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis
Am J Physiol Heart Circ Physiol,
August 1, 2007;
293(2):
H949 - H958.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. Germans, A. A.M. Wilde, P. A. Dijkmans, W. Chai, O. Kamp, Y. M. Pinto, and A. C. van Rossum
Structural Abnormalities of the Inferoseptal Left Ventricular Wall Detected by Cardiac Magnetic Resonance Imaging in Carriers of Hypertrophic Cardiomyopathy Mutations
J. Am. Coll. Cardiol.,
December 19, 2006;
48(12):
2518 - 2523.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. Rajan, S. S. Williams, G. Jagatheesan, R. P. H. Ahmed, G. Fuller-Bicer, A. Schwartz, B. J. Aronow, and D. F. Wieczorek
Microarray analysis of gene expression during early stages of mild and severe cardiac hypertrophy
Physiol Genomics,
November 21, 2006;
27(3):
309 - 317.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. H. Brown, Z. Zhou, L. Reshetnikova, H. Robinson, R. D. Yammani, L. S. Tobacman, and C. Cohen
Structure of the mid-region of tropomyosin: Bending and binding sites for actin
PNAS,
December 27, 2005;
102(52):
18878 - 18883.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. N. Chang, K. Harada, M. J. Ackerman, and J. D. Potter
Functional Consequences of Hypertrophic and Dilated Cardiomyopathy-causing Mutations in {alpha}-Tropomyosin
J. Biol. Chem.,
October 7, 2005;
280(40):
34343 - 34349.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. Wernicke, C. Thiel, C. M. Duja-Isac, K. V. Essin, M. Spindler, D. J. R. Nunez, R. Plehm, N. Wessel, A. Hammes, R.-J. Edwards, et al.
{alpha}-Tropomyosin mutations Asp175Asn and Glu180Gly affect cardiac function in transgenic rats in different ways
Am J Physiol Regulatory Integrative Comp Physiol,
September 1, 2004;
287(3):
R685 - R695.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. Coutu, C. N. Bennett, E. G. Favre, S. M. Day, and J. M. Metzger
Parvalbumin Corrects Slowed Relaxation in Adult Cardiac Myocytes Expressing Hypertrophic Cardiomyopathy-Linked {alpha}-Tropomyosin Mutations
Circ. Res.,
May 14, 2004;
94(9):
1235 - 1241.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. Maytum, F. Bathe, M. Konrad, and M. A. Geeves
Tropomyosin Exon 6b Is Troponin-specific and Required for Correct Acto-myosin Regulation
J. Biol. Chem.,
April 30, 2004;
279(18):
18203 - 18209.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|