α-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: A disease of the sarcomere

We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the alpha-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC) linked to chromosome 15q2. These findings implicated components of the troponin complex as candidate genes at other FHC loci, particularly cardiac troponin T, which was mapped in this study to chromosome 1q. Missense mutations (Ile79Asn; Arg92Gln) and a mutation in the splice donor sequence of intron 15 of the cardiac troponin T gene are also shown to cause FHC. Because alpha-tropomyosin and cardiac troponin T as well as beta myosin heavy chain mutations cause the same phenotype, we conclude that FHC is a disease of the sarcomere. Further, because the splice site mutation is predicted to function as a null allele, we suggest that abnormal stoichiometry of sarcomeric proteins can cause cardiac hypertrophy.

[1]  S. Sakiyama,et al.  Isolation and characterization of a cDNA that encodes mouse fibroblast tropomyosin isoform 2 , 1988, Molecular and cellular biology.

[2]  L. Fananapazir,et al.  Genotype-Phenotpe Correlations in Hypertrophic Cardiomyopathy Insights Provided by Comparisons of Kindreds With Distinct and Identical j3-Myosin Heavy Chain Gene Mutations , 2005 .

[3]  J. Lin,et al.  Isolation and characterization of cDNA clones encoding embryonic and adult isoforms of rat cardiac troponin T. , 1989, The Journal of biological chemistry.

[4]  D. Sheer,et al.  A cDNA encoding a muscle-type tropomyosin cloned from a human epithelial cell line: identity with human fibroblast tropomyosin TM1. , 1991, Biochemical and biophysical research communications.

[5]  R. Bonow,et al.  Hypertrophic cardiomyopathy. , 1987, Disease-a-month : DM.

[6]  J. Seidman,et al.  A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[7]  F. E. Weber,et al.  Human myosin-binding protein H (MyBP-H): complete primary sequence, genomic organization, and chromosomal localization. , 1993, Genomics.

[8]  L. Smillie,et al.  Amino acid sequence of rabbit cardiac troponin T. , 1986, The Journal of biological chemistry.

[9]  J. Seidman,et al.  Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes. , 1991, The New England journal of medicine.

[10]  C. Fyrberg,et al.  Drosophila melanogaster troponin-T mutations engender three distinct syndromes of myofibrillar abnormalities. , 1990, Journal of molecular biology.

[11]  Y. Nonomura,et al.  Electron microscopic and electrophoretic studies of a Drosophila muscle mutant wings-up B , 1981 .

[12]  J. Seidman,et al.  The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families , 1992, Nature Genetics.

[13]  B. Nadal-Ginard,et al.  Alpha-tropomyosin gene organization. Alternative splicing of duplicated isotype-specific exons accounts for the production of smooth and striated muscle isoforms. , 1987, The Journal of biological chemistry.

[14]  F. Samson,et al.  Molecular cloning and developmental expression of human cardiac troponin T , 1993, FEBS letters.

[15]  S. Solomon,et al.  Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. , 1989, The New England journal of medicine.

[16]  J. H. Collins,et al.  Bovine cardiac troponin T: amino acid sequences of the two isoforms. , 1987, Biochemistry.

[17]  M. Green.  Pre-mRNA splicing. , 1986, Annual review of genetics.

[18]  N. Sternberg,et al.  Using bacteriophage P1 system to clone high molecular weight genomic DNA. , 1992, Methods in enzymology.

[19]  T. Cooper,et al.  A single cardiac troponin T gene generates embryonic and adult isoforms via developmentally regulated alternate splicing. , 1985, The Journal of biological chemistry.

[20]  J. Ott,et al.  A computer program for linkage analysis of general human pedigrees. , 1976, American journal of human genetics.

[21]  S. Solomon,et al.  Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. , 1994, The Journal of clinical investigation.

[22]  A. M. Gordon,et al.  Deletion of the first 45 NH2-terminal residues of rabbit skeletal troponin T strengthens binding of troponin to immobilized tropomyosin. , 1991, The Journal of biological chemistry.

[23]  M. Davies.  Hypertrophic cardiomyopathy: one disease or several? , 1990, British heart journal.

[24]  J. Seidman,et al.  Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. , 1992, The New England journal of medicine.

[25]  J. Brisson,et al.  Interaction of tropomyosin and troponin T: a proton nuclear magnetic resonance study. , 1986, Biochemistry.

[26]  C. Gooding,et al.  Human hTM alpha gene: expression in muscle and nonmuscle tissue , 1988, Molecular and cellular biology.

[27]  B. Nadal-Ginard,et al.  Complete nucleotide sequence of the fast skeletal troponin T gene. Alternatively spliced exons exhibit unusual interspecies divergence. , 1986, Journal of molecular biology.

[28]  J. Beckmann,et al.  Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11 , 1993, Nature Genetics.

[29]  S. Hardy,et al.  Characterization of muscle and non muscle Xenopus laevis tropomyosin mRNAs transcribed from the same gene. Developmental and tissue-specific expression. , 1991, European journal of biochemistry.

[30]  H. Jockusch,et al.  Chromosomal Localization and Genomic Cloning of the Mouse α-Tropomyosin Gene Tpm-1 , 1993 .

[31]  D. Helfman,et al.  The molecular basis for tropomyosin isoform diversity , 1991, BioEssays : news and reviews in molecular, cellular and developmental biology.

[32]  L. Smillie,et al.  Primary structure of rabbit skeletal muscle troponin-T. Sequence determination of the NH2-terminal fragment CB3 and the complete sequence of troponin-T. , 1977, The Journal of biological chemistry.

[33]  S. Berget,et al.  Exon definition may facilitate splice site selection in RNAs with multiple exons. , 1990, Molecular and cellular biology.

[34]  J. Robbins,et al.  Troponin T Expression in Normal and Pressure-Loaded Fetal Sheep Heart , 1991, Pediatric Research.

[35]  C. Emerson,et al.  Developmental and muscle-specific regulation of avian fast skeletal troponin T isoform expression by mRNA splicing. , 1989, The Journal of biological chemistry.

[36]  George N. Phillips,et al.  Structure of co-crystals of tropomyosin and troponin , 1987, Nature.

[37]  J. Potter,et al.  Structural aspects of troponin-tropomyosin regulation of skeletal muscle contraction. , 1987, Annual review of biophysics and biophysical chemistry.

[38]  L. Smillie,et al.  Sequences of complete cDNAs encoding four variants of chicken skeletal muscle troponin T. , 1988, The Journal of biological chemistry.

[39]  P. Allen,et al.  Troponin T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle. , 1991, Circulation research.

[40]  J. Lin,et al.  Complete nucleotide sequence and structural organization of rat cardiac troponin T gene. A single gene generates embryonic and adult isoforms via developmentally regulated alternative splicing. , 1992, Journal of molecular biology.

[41]  Y. Ishii,et al.  Two-site attachment of troponin to pyrene-labeled tropomyosin. , 1991, The Journal of biological chemistry.

[42]  A. E. Oakeley,et al.  A cardiac troponin T epitope conserved across phyla. , 1992, The Journal of biological chemistry.

[43]  L. Kedes,et al.  Alternative splicing generates variants in important functional domains of human slow skeletal troponin T. , 1987, The Journal of biological chemistry.

[44]  J. Seidman,et al.  A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3 , 1993, Nature Genetics.

[45]  T. Parker,et al.  Growth factors, proto-oncogenes, and plasticity of the cardiac phenotype. , 1991, Annual review of physiology.