title: D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias.
abstract: Dilated cardiomyopathy (DCM) and malignant ventricular arrhythmias are important causes of congestive heart failure, heart transplantation, and sudden cardiac death in young patients. Cypher/ZASP is a cytoskeletal protein localized in the sarcomeric Z-line that has a pivotal role in maintaining adult cardiac structure and function. The putative mutation p.(D117N) in Cypher/ZASP has been suggested to cause systolic dysfunction, dilated left ventricle with hypertrabeculated myocardium, and intraventricular conduction disturbance, based on two reported sporadic cases. In two unrelated Bedouin families, one with pediatric DCM and the other with DCM and ventricular arrhythmias at young adulthood searching for the causative mutation by exome sequencing we identified the p.(D117N) variant in Cypher/ZASP. However, p.(D117N) did not segregate as the causative mutation in these families, i.e. it was not present in some patients and was found in several individuals who had no clinical manifestations. Furthermore, the carrier frequency in the Bedouin population of origin is estimated to be 5.2%, which is much higher than the incidence of idiopathic DCM in this population. Thus, our data support the notion that the p.(D117N) variant in Cypher/ZASP is not a causative mutation in the families tested by us. The results also indicates that at least in some cases, the p.(D117N) in Cypher/ZASP is not a causative mutation and the role of D117N in Cypher/ZASP in cardiac pathologies should be further clarified and re-evaluated.
authors.affiliation: Director of Pediatric Cardiac Imaging, Department of Pediatric Cardiology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Levitas
authors.affiliation: Department of Cardiology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Konstantino
authors.affiliation: Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Emad
authors.initials: E
authors.lastname: Muhammad
authors.affiliation: Sackler Faculty of Medicine, Department of Neurology, Tel-Aviv University, Ramat Aviv, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.affiliation: Department of Cardiology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Jean
authors.initials: J
authors.lastname: Marc Weinstein
authors.affiliation: Department of Cardiology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Guy
authors.initials: G
authors.lastname: Amit
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Regenerative Medicine & Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|National Institute of Biotechnology Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Etzion
authors.affiliation: Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|National Institute of Biotechnology Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Ruti
authors.initials: R
authors.lastname: Parvari
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D018912:Arabs; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D060588:LIM Domain Proteins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D018754:Ventricular Dysfunction / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C120696:LDB3 protein, human; D060588:LIM Domain Proteins