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.
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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 |
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