Codon 102 of the cardiac troponin T gene is a putative hot spot for mutations in familial hypertrophic cardiomyopathy.

BACKGROUND Familial hypertrophic cardiomyopathy is a phenotypically and genetically heterogeneous disease. In some families, the disease is linked to the CMH2 locus on chromosome 1q3, in which the cardiac troponin T gene (TNNT2) has been identified as the disease gene. The mutations found in this gene appear to be associated with incomplete penetrance and poor prognosis. Because mutational hot spots offer unique possibilities for analysis of genotype-phenotype correlations, new missense mutations that could define such hot spots in TNNT2 were looked for in unrelated French families with familial hypertrophic cardiomyopathy. METHODS AND RESULTS Family members were genotyped with microsatellite markers to detect linkage to the four known disease loci. In family 715, analyses showed linkage to CMH2 only. To accurately position potential mutations on TNNT2, its partial genomic organization was established. Screening for mutations was performed by single-strand conformation polymorphism analysis and sequencing. A new missense mutation, Arg102Leu, was identified in affected members of family 715 because of a G-->T transversion located in the 10th exon of the gene. Penetrance of this new mutation is complete; echocardiographic data show a wide range of hypertrophy; and there was no sudden cardiac death in this family. CONCLUSIONS The codon 102 of the TNNT2 gene is a putative mutational hot spot in familial hypertrophic cardiomyopathy and is associated with phenotypic variability. Analysis of more pedigrees carrying mutations in this codon is necessary to better characterize the clinical and prognostic implications of TNNT2 mutations.

[1]  J. Seidman,et al.  Mutations in the cardiac myosin binding protein–C gene on chromosome 11 cause familial hypertrophic cardiomyopathy , 1995, Nature Genetics.

[2]  J. Beckmann,et al.  Cardiac myosin binding protein–C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy , 1995, Nature Genetics.

[3]  M. Yacoub,et al.  Molecular cloning of human cardiac troponin T isoforms: expression in developing and failing heart. , 1995, Journal of molecular and cellular cardiology.

[4]  A. Marian,et al.  Recent advances in the molecular genetics of hypertrophic cardiomyopathy. , 1995, Circulation.

[5]  J. Seidman,et al.  Familial hypertrophic cardiomyopathy: a genetic model of cardiac hypertrophy. , 1995, Human molecular genetics.

[6]  J. Seidman,et al.  Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. , 1995, The New England journal of medicine.

[7]  S. Diriong,et al.  Human cardiac troponin T: cloning and expression of new isoforms in the normal and failing heart. , 1995, Circulation research.

[8]  M. Komajda,et al.  Molecular basis of familial cardiomyopathies. , 1995, Circulation.

[9]  Christine E. Seidman,et al.  α-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: A disease of the sarcomere , 1994, Cell.

[10]  P. Rogan,et al.  A new missense mutation, Arg719Gln, in the beta-cardiac heavy chain myosin gene of patients with familial hypertrophic cardiomyopathy. , 1994, Human molecular genetics.

[11]  Cécile Fizames,et al.  The 1993–94 Généthon human genetic linkage map , 1994, Nature Genetics.

[12]  M. Yacoub,et al.  Human cardiac troponin T: identification of fetal isoforms and assignment of the TNNT2 locus to chromosome 1q. , 1994, Genomics.

[13]  C. Hengstenberg,et al.  Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene. , 1993, The Journal of clinical investigation.

[14]  P. Brink,et al.  Identification of a new missense mutation at Arg403, a CpG mutation hotspot, in exon 13 of the beta-myosin heavy chain gene in hypertrophic cardiomyopathy. , 1993, Human molecular genetics.

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

[16]  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.

[17]  D. Barker,et al.  Restriction sites containing CpG show a higher frequency of polymorphism in human DNA , 1984, Cell.