Mutations in Cypher/ZASP in Patients with Dilated Cardiomyopathy and Left Ventricular Non-Compaction

Matteo Vatta, Bhagyalaxmi Mohapatra, Shinawe Jimenez, Ximena Sanchez, Georgine Faulkner, Zeev Perles, Gianfranco Sinagra, Jiuann Huey Lin, Thuy M. Vu, Qiang Zhou, Karla R. Bowles, Andrea Di Lenarda, Lisa Schimmenti, Michelle Fox, Michelle A. Chrisco, Ross T. Murphy, William McKenna, Perry Elliott, Neil E. Bowles, Ju Chen & 2 others Giorgio Valle, Jeffrey Towbin

Research output: Contribution to journalArticle

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Abstract

OBJECTIVES: We evaluated the role of Cypher/ZASP in the pathogenesis of dilated cardiomyopathy (DCM) with or without isolated non-compaction of the left ventricular myocardium (INLVM). BACKGROUND: Dilated cardiomyopathy, characterized by left ventricular dilation and systolic dysfunction with signs of heart failure, is genetically transmitted in 30% to 40% of cases. Genetic heterogeneity has been identified with mutations in multiple cytoskeletal and sarcomeric genes causing the phenotype. In addition, INLVM with a hypertrophic dilated left ventricle, ventricular dysfunction, and deep trabeculations, is also inherited, and the genes identified to date differ from those causing DCM. Cypher/ZASP is a newly identified gene encoding a protein that is a component of the Z-line in both skeletal and cardiac muscle. METHODS: Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and physical examination. In addition, levels of the muscular isoform of creatine kinase were measured to evaluate for skeletal muscle involvement. Cypher/ZASP was screened by denaturing high performance liquid chromatography (DHPLC) and direct deoxyribonucleic acid sequencing. RESULTS We identified and screened 100 probands with left ventricular dysfunction. Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM. In vitro studies showed cytoskeleton disarray in cells transfected with mutated Cypher/ZASP. CONCLUSIONS: These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and identify a mechanistic basis.

Original languageEnglish (US)
Pages (from-to)2014-2027
Number of pages14
JournalJournal of the American College of Cardiology
Volume42
Issue number11
DOIs
StatePublished - Dec 3 2003
Externally publishedYes

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Isolated Noncompaction of the Ventricular Myocardium
Dilated Cardiomyopathy
Mutation
Left Ventricular Dysfunction
Skeletal Muscle
Genes
Genetic Heterogeneity
Creatine Kinase
Cytoskeleton
Physical Examination
Heart Ventricles
Dilatation
Myocardium
Electrocardiography
Protein Isoforms
Heart Failure
High Pressure Liquid Chromatography
Phenotype
DNA
Proteins

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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Mutations in Cypher/ZASP in Patients with Dilated Cardiomyopathy and Left Ventricular Non-Compaction. / Vatta, Matteo; Mohapatra, Bhagyalaxmi; Jimenez, Shinawe; Sanchez, Ximena; Faulkner, Georgine; Perles, Zeev; Sinagra, Gianfranco; Lin, Jiuann Huey; Vu, Thuy M.; Zhou, Qiang; Bowles, Karla R.; Di Lenarda, Andrea; Schimmenti, Lisa; Fox, Michelle; Chrisco, Michelle A.; Murphy, Ross T.; McKenna, William; Elliott, Perry; Bowles, Neil E.; Chen, Ju; Valle, Giorgio; Towbin, Jeffrey.

In: Journal of the American College of Cardiology, Vol. 42, No. 11, 03.12.2003, p. 2014-2027.

Research output: Contribution to journalArticle

Vatta, M, Mohapatra, B, Jimenez, S, Sanchez, X, Faulkner, G, Perles, Z, Sinagra, G, Lin, JH, Vu, TM, Zhou, Q, Bowles, KR, Di Lenarda, A, Schimmenti, L, Fox, M, Chrisco, MA, Murphy, RT, McKenna, W, Elliott, P, Bowles, NE, Chen, J, Valle, G & Towbin, J 2003, 'Mutations in Cypher/ZASP in Patients with Dilated Cardiomyopathy and Left Ventricular Non-Compaction', Journal of the American College of Cardiology, vol. 42, no. 11, pp. 2014-2027. https://doi.org/10.1016/j.jacc.2003.10.021
Vatta, Matteo ; Mohapatra, Bhagyalaxmi ; Jimenez, Shinawe ; Sanchez, Ximena ; Faulkner, Georgine ; Perles, Zeev ; Sinagra, Gianfranco ; Lin, Jiuann Huey ; Vu, Thuy M. ; Zhou, Qiang ; Bowles, Karla R. ; Di Lenarda, Andrea ; Schimmenti, Lisa ; Fox, Michelle ; Chrisco, Michelle A. ; Murphy, Ross T. ; McKenna, William ; Elliott, Perry ; Bowles, Neil E. ; Chen, Ju ; Valle, Giorgio ; Towbin, Jeffrey. / Mutations in Cypher/ZASP in Patients with Dilated Cardiomyopathy and Left Ventricular Non-Compaction. In: Journal of the American College of Cardiology. 2003 ; Vol. 42, No. 11. pp. 2014-2027.
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abstract = "OBJECTIVES: We evaluated the role of Cypher/ZASP in the pathogenesis of dilated cardiomyopathy (DCM) with or without isolated non-compaction of the left ventricular myocardium (INLVM). BACKGROUND: Dilated cardiomyopathy, characterized by left ventricular dilation and systolic dysfunction with signs of heart failure, is genetically transmitted in 30{\%} to 40{\%} of cases. Genetic heterogeneity has been identified with mutations in multiple cytoskeletal and sarcomeric genes causing the phenotype. In addition, INLVM with a hypertrophic dilated left ventricle, ventricular dysfunction, and deep trabeculations, is also inherited, and the genes identified to date differ from those causing DCM. Cypher/ZASP is a newly identified gene encoding a protein that is a component of the Z-line in both skeletal and cardiac muscle. METHODS: Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and physical examination. In addition, levels of the muscular isoform of creatine kinase were measured to evaluate for skeletal muscle involvement. Cypher/ZASP was screened by denaturing high performance liquid chromatography (DHPLC) and direct deoxyribonucleic acid sequencing. RESULTS We identified and screened 100 probands with left ventricular dysfunction. Five mutations in six probands (6{\%} of cases) were identified in patients with familial or sporadic DCM or INLVM. In vitro studies showed cytoskeleton disarray in cells transfected with mutated Cypher/ZASP. CONCLUSIONS: These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and identify a mechanistic basis.",
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TY - JOUR

T1 - Mutations in Cypher/ZASP in Patients with Dilated Cardiomyopathy and Left Ventricular Non-Compaction

AU - Vatta, Matteo

AU - Mohapatra, Bhagyalaxmi

AU - Jimenez, Shinawe

AU - Sanchez, Ximena

AU - Faulkner, Georgine

AU - Perles, Zeev

AU - Sinagra, Gianfranco

AU - Lin, Jiuann Huey

AU - Vu, Thuy M.

AU - Zhou, Qiang

AU - Bowles, Karla R.

AU - Di Lenarda, Andrea

AU - Schimmenti, Lisa

AU - Fox, Michelle

AU - Chrisco, Michelle A.

AU - Murphy, Ross T.

AU - McKenna, William

AU - Elliott, Perry

AU - Bowles, Neil E.

AU - Chen, Ju

AU - Valle, Giorgio

AU - Towbin, Jeffrey

PY - 2003/12/3

Y1 - 2003/12/3

N2 - OBJECTIVES: We evaluated the role of Cypher/ZASP in the pathogenesis of dilated cardiomyopathy (DCM) with or without isolated non-compaction of the left ventricular myocardium (INLVM). BACKGROUND: Dilated cardiomyopathy, characterized by left ventricular dilation and systolic dysfunction with signs of heart failure, is genetically transmitted in 30% to 40% of cases. Genetic heterogeneity has been identified with mutations in multiple cytoskeletal and sarcomeric genes causing the phenotype. In addition, INLVM with a hypertrophic dilated left ventricle, ventricular dysfunction, and deep trabeculations, is also inherited, and the genes identified to date differ from those causing DCM. Cypher/ZASP is a newly identified gene encoding a protein that is a component of the Z-line in both skeletal and cardiac muscle. METHODS: Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and physical examination. In addition, levels of the muscular isoform of creatine kinase were measured to evaluate for skeletal muscle involvement. Cypher/ZASP was screened by denaturing high performance liquid chromatography (DHPLC) and direct deoxyribonucleic acid sequencing. RESULTS We identified and screened 100 probands with left ventricular dysfunction. Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM. In vitro studies showed cytoskeleton disarray in cells transfected with mutated Cypher/ZASP. CONCLUSIONS: These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and identify a mechanistic basis.

AB - OBJECTIVES: We evaluated the role of Cypher/ZASP in the pathogenesis of dilated cardiomyopathy (DCM) with or without isolated non-compaction of the left ventricular myocardium (INLVM). BACKGROUND: Dilated cardiomyopathy, characterized by left ventricular dilation and systolic dysfunction with signs of heart failure, is genetically transmitted in 30% to 40% of cases. Genetic heterogeneity has been identified with mutations in multiple cytoskeletal and sarcomeric genes causing the phenotype. In addition, INLVM with a hypertrophic dilated left ventricle, ventricular dysfunction, and deep trabeculations, is also inherited, and the genes identified to date differ from those causing DCM. Cypher/ZASP is a newly identified gene encoding a protein that is a component of the Z-line in both skeletal and cardiac muscle. METHODS: Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and physical examination. In addition, levels of the muscular isoform of creatine kinase were measured to evaluate for skeletal muscle involvement. Cypher/ZASP was screened by denaturing high performance liquid chromatography (DHPLC) and direct deoxyribonucleic acid sequencing. RESULTS We identified and screened 100 probands with left ventricular dysfunction. Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM. In vitro studies showed cytoskeleton disarray in cells transfected with mutated Cypher/ZASP. CONCLUSIONS: These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and identify a mechanistic basis.

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U2 - 10.1016/j.jacc.2003.10.021

DO - 10.1016/j.jacc.2003.10.021

M3 - Article

VL - 42

SP - 2014

EP - 2027

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

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