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.
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References
Iacoviello M, Monitillo F : Non-invasive evaluation of arrhythmic risk in dilated cardiomyopathy: from imaging to electrocardiographic measures. World J Cardiol 2014; 6: 562–576.
Vatta M, Mohapatra B, Jimenez S et al: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol 2003; 42: 2014–2027.
Xing Y, Ichida F, Matsuoka T et al: Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity. Mol Genet Metab 2006; 88: 71–77.
Faulkner G, Pallavicini A, Formentin E et al: ZASP: a new Z-band alternatively spliced PDZ-motif protein. J Cell Biol 1999; 146: 465–475.
Klaavuniemi T, Ylanne J : Zasp/Cypher internal ZM-motif containing fragments are sufficient to co-localize with alpha-actinin–analysis of patient mutations. Exp Cell Res 2006; 312: 1299–1311.
Martinelli VC, Kyle WB, Kojic S et al: ZASP interacts with the mechanosensing protein Ankrd2 and p53 in the signalling network of striated muscle. PLoS One 2014; 9: e92259.
Zhou Q, Chu PH, Huang C et al: Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy. J Cell Biol 2001; 155: 605–612.
Zheng M, Cheng H, Li X et al: Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death. Hum Mol Genet 2009; 18: 701–713.
Xi Y, Ai T, De Lange E et al: Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction. Circ Arrhythm Electrophysiol 2012; 5: 1017–1026.
Schiller NB, Shah PM, Crawford M et al: Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989; 2: 358–367.
Henry WL, Gardin JM, Ware JH : Echocardiographic measurements in normal subjects from infancy to old age. Circulation 1980; 62: 1054–1061.
Richardson P, McKenna W, Bristow M et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996; 93: 841–842.
Jenni R, Oechslin EN, van der Loo B : Isolated ventricular non-compaction of the myocardium in adults. Heart 2007; 93: 11–15.
Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA : Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart 2001; 86: 666–671.
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We thank the family members for their participation. The study was supported by a nuclear grant of Ben-Gurion University of the Negev (AL, JMW, YE, and RP).
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Levitas, A., Konstantino, Y., Muhammad, E. et al. D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias. Eur J Hum Genet 24, 666–671 (2016). https://doi.org/10.1038/ejhg.2015.195
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DOI: https://doi.org/10.1038/ejhg.2015.195
