Mutations in MYOZ1 As Well As MYOZ2 Encoding

Molecular Genetics and Metabolism 91 (2007) 207–208 www.elsevier.com/locate/ymgme Letter to the Editor

Mutations in MYOZ1 as well as MYOZ2 encoding the (as described here) the probability that the respective calsarcins are not associated with idiopathic and familial candidate gene does not constitute a relevant disease gene dilated cardiomyopathy is higher when screening a cohort with familial disease. The most important point to address to the work de- Dear Editor, scribed by Arola et al. [1] is that the analysis should not be restricted to MYOZ1 when investigating the genetic eti- We have read the article of Arola and colleagues [1] with ology of DCM. Indeed, MYOZ1 is abundantly expressed great interest. The authors report a candidate gene in skeletal muscle, but cardiomyocytes reveal a very weak approach in the MYOZ1 gene encoding calsarcin-2 in mRNA expression of MYOZ1 [5]. Conversely, MYOZ2 185 patients with idiopathic dilated cardiomyopathy encoding calsarcin-1 is predominantly expressed in cardio- (iDCM). No disease associated mutation was identified myocytes and to lesser extends in skeletal muscle [5,6]. by use of denaturing high-performance liquid chromatog- Calsarcin-1 is located at the sarcomeric Z-disk and inter- raphy (DHPLC). acts with DCM disease genes like telethonin and a-actinin. We have examined a cohort of 61 patients with proven Furthermore, conditional MYOZ2 knock out mice reveal familial dilated cardiomyopathy (fDCM). fDCM was diag- heart failure and extensive dilation of both ventricles after nosed when two or more affected relatives were present in aortic banding [7]. Therefore, MYOZ2 represents a more one family (range: 2–7; mean: 3.2). Clinical examination plausible candidate gene for DCM. was performed according to the European guidelines for However, taking together the results from Arola et al. investigation of familial dilated cardiomyopathy [2] as de- [1] with results from a recent candidate gene approach ana- scribed previously [3]. We directly sequenced all coding lyzing MYOZ2 [8], pathogenic mutations in MYOZ1 and exons (2–6) with flanking intronic portions of MYOZ1 MYOZ2 could not be identified in 185 and 19 patients with by use of ABI Big Dye chemistry as described in detail in idiopathic DCM patients, respectively. Additionally, we [4]. In contrast to Arola et al. [1], we additionally analyzed have excluded mutations in both genes in a cohort of 61 exonic fragments (2–6) of MYOZ2 encoding the cardiac carefully selected families with fDCM using a highly sensi- calsarcin-1. tive screening method. We also identified the L255L (CTG > CTT) variant as In conclusion, one can state that mutations in MYOZ1 described in [1]. Five fDCM patients were heterozygous and MYOZ2 are at least very rare events as an underlying L255L carriers. However, no other genetic variant in disease mechanism for idiopathic or familial DCM. MYOZ1 could be detected by us. Sequencing of MYOZ2 We acknowledge the support of the Berlin Institute for resulted in identification of two synonymous polymor- Heart Research (BIHR-VH-VI 152) funded by the Helm- phisms (A79A and E153E). These heterozygous variants holtz Gemeinschaft, research grant from Charite´-Universi- were uniquely detected in two individuals with fDCM. ta¨tsmedizin Berlin and the German Heart Failure Network All identified polymorphisms in MYOZ1 and MYOZ2 (GHFN). are represented in Fig. 1. Although DHPLC has been proven to be a sensitive References method for mutational analysis, one can not completely ex- clude that some variants might have escaped the analysis of [1] A.M. Arola, X. Sanchez, R.T. Murphy, E. Hasle, H. Li, P.M. Elliot, Arola and colleagues. However, direct sequencing consti- W.J. McKenna, J.A. Towbin, N.E. Bowles, Mutations in PDLIM3 and MYOZ1 encoding myocyte Z line proteins are infrequently found tutes the gold standard of genetic analysis almost excluding in idiopathic dilated cardiomyopathy, Mol. Genet. Metab. (2007), false negative results in candidate gene approaches. Fur- doi:10.1016/j.ymgme.2006.12.008. thermore, screening in patients with a hereditary form of [2] L. Mestroni, B. Maisch, W.J. McKenna, K. Schwartz, P. Charron, C. DCM offers several advantages: first, the prevalence of Rocco, F. Tesson, A. Richter, A. Wilke, M. Komajda, Guidelines for pathogenic mutations should be higher in patients with the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on familial DCM. Further, identified unknown variants can Familial Dilated Cardiomyopathy, Eur. Heart J. 20 (1999) 93–102. easily be checked for co-segregation with the disease in [3] A. Perrot, H.H. Sigusch, H. Nagele, J. Genschel, H.B. Lehmkuhl, R. the family pedigrees. Secondly, in case of negative results Hetzer, C. Geier, V. Leon Perez, D. Reinhard, R. Dietz, K.J. Osterziel,

[4] C. Geier, A. Perrot, C. Ozcelik, P. Binner, D. Counsell, K. Hoffmann, MYOZ1 (Calsarcin-2) a B. Pilz, Y. Martiniak, K. Gehmlich, P.F. van der Ven, D.O. Furst, A. S50S L255L Vornwald, E. von Hodenberg, P. Nurnberg, T. Scheffold, R. Dietz, K.J. Osterziel, Mutations in the human muscle LIM protein gene in bp 347 91 179 250 166 508 families with hypertrophic cardiomyopathy, Circulation 107 (2003) 1390–1395. 1 2 3 4 5 6 [5] G. Faulkner, A. Pallavicini, A. Comelli, M. Salamon, G. Bortoletto, C. Ievolella, S. Trevisan, S. Kojic, F. Dalla Vecchia, P. Laveder, G. Valle, G. Lanfranchi, FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle, J. Biol. Chem. 275 (2000) 41234–41242. [6] N. Frey, J.A. Richardson, E.N. Olson, Calsarcins, a novel family of NH2 COOH sarcomeric calcineurin-binding proteins, Proc. Natl. Acad. Sci. USA 97 aa 1 75 171 299 (2000) 14632–14637.

telethonin α-actinin myotilin [7] N. Frey, T. Barrientos, J.M. Shelton, D. Frank, H. Rutten, D. filaminC filamin C Gehring, C. Kuhn, M. Lutz, B. Rothermel, R. Bassel-Duby, J.A. Richardson, H.A. Katus, J.A. Hill, E.N. Olson, Mice lacking calsarcin- b MYOZ2 (Calsarcin-1) 1 are sensitized to calcineurin signaling and show accelerated cardio- A79A c.246-18A>G E153E myopathy in response to pathological biomechanical stress, Nat. Med. (rs17851524) (rs11721566) (rs7687613) 12 (2004) 1336–1343. [8] R. Zeller, B.T. Ivandic, P. Ehlermann, O. Mucke, C. Zugck, A. bp 117 76 170 130 184 1815 Remppis, E. Giannitsis, H.A. Katus, D. Weichenhan, Large-scale 1 2 3 4 5 6 mutation screening in patients with dilated or hypertrophic cardiomyopathy: a pilot study using DGGE, J. Mol. Med. 84 (2006) 682–691.

Maximilian G. Posch* Andreas Perrot NH2 COOH Rainer Dietz aa 1 153 200 217 240 264 Cemil O¨ zcelik telethonin α-actinin calcineurin Charite´ – Universita¨tsmedizin Berlin/Cardiology at Campus calcineurin filamin C Buch & Virchow Klinikum, Helios-Kliniken and Fig. 1. Schematic representation of the gene structure of MYOZ1 Max-Delbru¨ck Center for Molecular Medicine, (NM_021245) encoding calsarcin-2 and MYOZ2 (NM_016599) encoding Wiltbergstrasse 50, 13125 Berlin, Germany calsarcin-1 with the variants identified by Arola et al. [1] and us indicated. E-mail address: [email protected] Open boxes represent exons with the number of coding nucleotides above (M.G. Posch). and UTRs shaded. The S50S variant in MYOZ1 was described by Arola et al. [1], whereas the L255L variant in MYOZ1 was identified by Arola Sabine Pankuweit et al. and us (allelic frequency 8.2%). The A79A and E153E polymor- Volker Ruppert phisms in MYOZ2 were identified in two patients of our fDCM cohort, respectively. Many different and overlapping protein–protein interaction Anette Richter domains have been described for calsarcin-1 and calsarcin-2 in different Bernhard Maisch studies [5,6]. Department of Internal Medicine and Cardiology, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany H.H. Schmidt, Genetic and phenotypic analysis of dilated cardiomyopathy with conduction system disease: demand for strategies in the management of presymptomatic lamin A/C mutant carriers, Eur. J. Received 26 February 2007; accepted 26 February 2007 Heart Fail. 8 (2006) 484–493. Available online 16 April 2007

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