Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin - PubMed (original) (raw)

Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin

J Martijn Bos et al. Mol Genet Metab. 2006 May.

Abstract

Background: TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded telethonin are Z-disc proteins essential for the structural organization of the cardiac sarcomere and the cardiomyocyte's stretch sensor. All three genes have been established as cardiomyopathy-associated genes for both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Here, we sought to characterize the frequency, spectrum, and phenotype associated with HCM-associated mutations in these three genes in a large cohort of unrelated patients evaluated at a single tertiary outpatient center.

Methods: DNA was obtained from 389 patients with HCM (215 male, left ventricular wall thickness of 21.6+/-6 mm) and analyzed for mutations involving all translated exons of CSRP3 and TCAP and targeted HCM-associated exons (2, 3, 4, and 14) of TTN using polymerase chain reaction (PCR), denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing. Clinical data were extracted from patient records and maintained independent of the genotype.

Results: Overall, 16 patients (4.1%) harbored a Z-disc mutation: 12 had a MLP mutation and 4 patients a TCAP mutation. No TTN mutations were detected. Seven patients were also found to have a concomitant myofilament mutation. Seven patients with a MLP-mutation were found to harbor the DCM-associated, functionally characterized W4R mutation. W4R-MLP was also noted in a single white control subject. Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM.

Conclusions: Approximately 4.1% of unrelated patients had HCM-associated MLP or TCAP mutations. MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease-causing mutation. The precise role of W4R-MLP in the pathogenesis of either DCM or HCM warrants further investigation.

PubMed Disclaimer

Figures

Fig. 1

Fig. 1

Topological schematic of muscle LIM protein and telethonin. Shown are the important domains of the protein. For MLP, the TCAP-binding domain, both LIM-domains and its nuclear localization signal (NLS) are shown. For telethonin, the MLP -, titin-, and minK-binding domains are shown. Amino-acid localization of the specific domains between parentheses.

Fig. 2

Fig. 2

Schematic representation of mutations in muscle LIM protein and telethonin. Representation of mutations found in our cohort of 389 patients with HCM. The L44P-MLP has been previously published as a HCM-associated mutation. The W4R-MLP mutation has been previously published and functionally characterized in patients with DCM. Novel mutations are indicated with an asterisk.

Fig. 3

Fig. 3

Degree of hypertrophy (A), degree of left ventricular outflow tract obstruction (B), and age at diagnosis (C) for genotyped subjects. Genotyped patients with hypertrophic cardiomyopathy are grouped on the _X_-axis as hosting as hosting no putative mutation (genotype negative), hosting a myofilament mutation (myofilament-HCM), a MLP-mutation or a TCAP-mutation. Unless otherwise noted, all pair wise comparisons are not statistically significant. *p < 0.05 compared to all other groups.

Comment in

Similar articles

Cited by

References

    1. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002;287:1308–1320. - PubMed
    1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. 1995;92:785–789. - PubMed
    1. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg H, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006. - PubMed
    1. Poetter K, Jiang H, Hassanzadeh S, Master SR, Chang A, Dalakas MC, Rayment I, Sellers JR, Fananapazir L, Epstein ND. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat. Genet. 1996;13:63–69. - PubMed
    1. Watkins H, Conner D, Thierfelder L, Jarcho JA, MacRae C, McKenna WJ, Maron BJ, Seidman JG, Seidman CE. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat. Genet. 1995;11:434–437. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources