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The Role of Sarcomere Gene Mutations in Patients with Idiopathic Dilated Cardiomyopathy

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The Role of Sarcomere Gene Mutations in Patients with Idiopathic Dilated Cardiomyopathy European Journal of Human Genetics (2009) 17, 1241 – 1249 & 2009 Macmillan Publishers Limited All rights reserved 1018-4813/09 $32.00 www.nature.com/ejhg ARTICLE The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy Daniel Vega Møller1, Paal Skytt Andersen2, Paula Hedley2,3, Mads Kristian Ersbøll1, Henning Bundgaard1, Johanna Moolman-Smook3, Michael Christiansen2 and Lars Køber1 1Department of Cardiology, Rigshospitalet, University of Copenhagen, Denmark; 2Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, Denmark; 3Department of Biomedical Sciences, MRC/US Centre for Molecular and Cellular Biology, University of Stellenbosch Health Sciences Faculty, Tygerberg, South Africa We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease. European Journal of Human Genetics (2009) 17, 1241–1249; doi:10.1038/ejhg.2009.34; published online 18 March 2009 Keywords: cardiomyopathies; dilated; heart failure; sarcomere gene mutations; DNA mutational analysis Introduction formerly been estimated at 36.5/100 000, with an incidence Dilated cardiomyopathy (DCM) is characterized primarily of 4–8/100 000 person-year.1 About 20–35% of the IDC by left ventricular dilatation and impaired systolic function cases are familial forms (FDC).2,3 FDC is defined as IDC in and is one of the leading causes of heart failure with high two or more closely related family members or, when morbidity and mortality. In the absence of significant involving a first-degree relative of an IDC patient, with a coronary artery disease or other discernible causes, its well-documented unexplained sudden death at o35 years origin is considered unknown and termed idiopathic DCM of age.4 Disease-causing genes in FDC predominantly (IDC). The prevalence of IDC in the United States has follow autosomal dominant inheritance patterns, but there have also been reports of X-linked, autosomal recessive and Correspondence: Dr DV Møller, Department of Cardiology, Rigshospitalet, mitochondrial inheritance. The penetrance and presenta- Blegdamsvej 9, 2100 Copenhagen O, Denmark. tion of FDC is highly variable concerning the functional Tel: þ 45 35458619; Fax: þ 45 35452549; impairment, extent of cardiac involvement and the E-mail: [email protected] Received 10 October 2008; revised 29 January 2009; accepted 5 February presence of other clinical manifestations, such as woolly 2009; published online 18 March 2009 hair or skeletal muscle disorders. Sarcomere gene mutations in dilated cardiomyopathy DV Mller et al 1242 Genes underlying IDC have been identified from linkage Controls were 100 randomly selected, ethnically as well as candidate gene studies, and include those matched DNA samples extracted from Danish Guthrie coding for proteins involved in the cytoskeleton (desmin,5 cards. d-sarcoglycan,6 dystrophin,7 desmoplakin8 and metavincu- The study conforms to the principles outlined in the lin9), the Z-disk (muscle LIM protein,10 a-actinin-211 and Declaration of Helsinki and was approved by the Scientific Cypher/ZASP12), the nuclear envelope (lamin A/C13) and Ethics Committee of Copenhagen and Frederiksberg ion conduction (phospholamban,14 SUR2A15 and the (No.(KF) 01263289). 16 Nav1.5 ion channel ). Although genes encoding sarco- meric proteins were traditionally considered to be involved Molecular genetic studies in hypertrophic cardiomyopathy,17 since 1998 it has also Patients were genetically screened at Statens Serum been known that mutations in these genes can cause Institut, Copenhagen, for variants in the coding regions IDC.18 Thus, mutations in the genes coding for the of the genes MYH7 (GenBank accession no. M57965.1), a- and b-myosin heavy chains,19 a-cardiac actin,18 a-tropo- MYBPC3 (GenBank accession no. U91629.1), MYL2 myosin,20 troponin T,21 troponin I,22 troponin C,23 titin,24 (GenBank accession no. NG_007554.1), MYL3 (GenBank myosin-binding protein C25 and telethonin10 have been accession no. NG_007555.1), TPM1 (GenBank shown to cause IDC. accession no. NG_007557.1), TNNT2 (GenBank accession However, the extent of sarcomeric gene involvement and no. NM_001001430.1), ACTC (GenBank accession no. its role in DCM remain largely unknown as most genetic NG_007553.1),CSRP3(GenBank accession no. NM_003476) studies in DCM have focussed on mutation screening of and TNNI3 (GenBank accession no. X90780.1). All patients single genes, rather than on comprehensive screening of were screened in LMNA (GenBank accession no. several sarcomeric genes. For this reason, we examined a NM_170707.1) without discovery of any variants in the cohort of IDC patients for mutations in nine prominent probands with sarcomere gene mutations. sarcomeric genes. Genomic DNA was isolated from whole blood samples (Qiagen, Germany). Intron-specific primers (available upon request) were used to amplify the coding regions Materials and methods by PCR. Amplified products were screened for mutations Subjects and clinical investigations by capillary electrophoresis single strand conformation Patients were recruited at a tertiary heart centre at the polymorphism27 and by subsequent bidirectional University Hospital, Rigshospitalet in Copenhagen, DNA sequencing of aberrant conformers on an ABI Denmark, and all gave written informed consent. All 31 3100 (Applied Biosystems, Foster City, CA, USA). The cases were unrelated and Caucasian, with 22 FDC and 9 frequency of all identified variants was determined in 100 non-FDC index patients; all suffered from heart failure and Danish controls as well as in family members of the underwent a comprehensive clinical assessment, compris- probands. ing detailed clinical and familial history, physical exam- A sequence variant was considered disease causing if ination, two-dimensional echocardiography, 12-lead ECG, (1) it resulted in a missense mutation, reading frame shift, 24-h Holter monitoring, exercise testing and standard or affected a canonical splice site; (2) it affected a conserved laboratory investigations, including creatine kinase and amino acid; (3) the mutation co-segregated with the iron studies. Coronary angiography was performed in all disease in affected family members; (4) it was not identified index patients. Patients with coronary disease, systemic among 100 ethnically matched controls, and (5) it was arterial hypertension, primary valvular disease, pericardial not described earlier as a polymorphism in dbSNP disease, cor pulmonale or a history of excess alcohol (www.ncbi.nlm.nih.gov/SNP) or the Harvard Sarcomere consumption were excluded. The diagnostic criteria were mutation database (www.cardiogenomics.org) or (6) if the left ventricular end-diastolic diameter (LVEDd) correspond- mutation had been described earlier as disease causing. In ing to a value above 3.1 cm/m2 (indexed to body surface the absence of more than two affected family members for area using the Mosteller formula26) and fractional short- segregation analysis, disease association was presumed if all ening o25% and/or left ventricular ejection fraction other criteria were met. (LVEF) o45%. Furthermore, we examined the hospital The effect of intronic variants on the splicing of records of the index patients carefully to ensure that the adjacent exons was analysed in silico by NetGene2 probands represented true IDC cases and not cases of (www.cbs.dtu.dk/services/NetGene2/) using default parameters. ‘burnt-out’ HCM. This included any history of chest pain, left ventricular hypertrophy on ECG and wall thickness in the first echocardiography performed. Results Relatives of the index cases were offered a physical Cohort characteristics examination, two-dimensional echocardiography, 12-lead The group consisted of 22 men and 9 women, with a mean ECG, exercise testing and standard laboratory investigations. LVEF of 19.2±7.8 and LVEDd of 71.5±9.5 mm, with a European Journal of Human Genetics Sarcomere gene mutations in dilated cardiomyopathy DV Mller et al 1243 mean age at the time of diagnosis of 41.5±8.5 years. Twenty- the exchange of a highly conserved basic amino acid with an two (71%) of them underwent HTX before or soon after acidic amino acid. As residue 637 is located in the myosin inclusion in the study. In 61% (19 probands), myocardial loop, which interacts with
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