Author + information
- Received July 15, 2003
- Revision received October 6, 2003
- Accepted October 9, 2003
- Published online December 3, 2003.
- Matteo Vatta, PhD*,
- Bhagyalaxmi Mohapatra, PhD*,
- Shinawe Jimenez, MD*,
- Ximena Sanchez, PhD*,
- Georgine Faulkner, PhD‡,
- Zeev Perles, MD*,
- Gianfranco Sinagra, MD§,
- Jiuann-Huey Lin, MD*,
- Thuy M Vu, BS*,
- Qiang Zhou, PhD∥,
- Karla R Bowles, PhD*,
- Andrea Di Lenarda, MD§,
- Lisa Schimmenti, MD¶,
- Michelle Fox, MS∥,
- Michelle A Chrisco, BS*,
- Ross T Murphy, MD#,
- William McKenna, MD#,
- Perry Elliott, MD#,
- Neil E Bowles, PhD*,
- Ju Chen, PhD∥,
- Giorgio Valle, PhD** and
- Jeffrey A Towbin, MD, FACC*,†,* ()
- ↵*Reprint requests and correspondence:
Dr. Jeffrey A. Towbin, Pediatric Cardiology, Texas Children's Hospital, 6621 Fannin Street, F.C. 430.09, Houston, Texas 77030, USA.
Objectives We evaluated the role of Cypher/ZASPin 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/ZASPis 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/ZASPwas 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/ZASPcan cause DCM and INLVM and identify a mechanistic basis.
☆ This work was funded by grants from the International Society for Heart and Lung Transplantation (Dr. Vatta), the American Heart Association (Dr. Bowles), the Muscular Dystrophy Association (Drs. Towbin, Bowles, and Chen), the National Institutes of Health, National Heart, Lung, and Blood Institute (Dr. Towbin: R01-HL62570 and PO1 HL67155; Dr. Chen: 1R01-HL66100), and the John Patrick Albright Foundation (Dr. Towbin). Dr. Towbin is also supported by the Texas Children's Hospital Foundation Chair in Pediatric Cardiovascular Research, the Abercrombie Pediatric Cardiology Fund of Texas Children's Hospital, and contributions from the Powers family. The financial support of Telethon-Italy to Dr. Faulkner (Grant 1278) and Dr. Valle (Grant B.57) is gratefully acknowledged.
Drs. Vatta, Mohapatra, and Jimenez contributed equally to the work. Joel S. Karliner acted as Guest Editor for this paper.
- Received July 15, 2003.
- Revision received October 6, 2003.
- Accepted October 9, 2003.
- American College of Cardiology Foundation