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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

View larger version (17K): [in a new window]   Figure 1 Five generation pedigree of the familial hypertrophic cardiomyopathy family. Pedigree symbols: squares = males; circles = females; symbols with diagonal slash = deceased family members; filled symbols = individuals with documented hypertrophic cardiomyopathy; dot within symbol = obligate carrier of the genetic defect; unfilled symbols = individuals without cardiac hypertrophy. Underneath the symbols are indicated the age (years) of sudden death and the genetically defined carriers of the mutation with E62Q (Glu62Gln). Bars = the haplotypes and numbers the alleles length (in basepairs) of the markers D15S159 (upper) and D15S993 (lower); filled bars = the risk haplotype 165 to 181.

View larger version (23K): [in a new window]   Figure 2 This figure has been redrawn according to Michele et al. 2000 (26), and represents the predicted coiled-coil structure of the alpha-tropomyosin gene (TPM1) alpha helix. The positions a to g represent the amino acids sequence of the heptad repeat that stretches along the entire alpha-tropomyosin protein. The view starts from the N-terminus (position a) of the tropomyosin protein going down the axis of the tropomyosin dimer (position g). The dotted lines represent the stabilizing interaction of charged amino acids between two tropomyosin molecules to form the coiled-coil dimer. Mutations associated with familial hypertrophic cardiomyopathy (bold) or dilated cardiomyopathy (italic) are indicated in the figure. The mutation Glu62Gln identified in this study is underlined.