Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy Hu Wang, Zhaohui Li, Jizheng Wang, Kai Sun, Qiqiong Cui, Lei Song, Yubao.

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Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy Hu Wang, Zhaohui Li, Jizheng Wang, Kai Sun, Qiqiong Cui, Lei Song, Yubao Zou, Xiaojian Wang, Xuan Liu, Rutai Hui, Yuxin Fan The American Journal of Human Genetics Volume 87, Issue 5, Pages 687-693 (November 2010) DOI: 10.1016/j.ajhg.2010.10.002 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Mutation Analysis of NEXN in Familial Hypertrophic Cardiomyopathy Filled symbols indicate clinically affected individuals; open symbols indicate unaffected individuals; half-filled symbol indicates suspected affected individual; a slash through a circle or square indicates a deceased individual; plus (+) and minus (−) signs indicate the presence or absence of a mutation in NEXN, respectively; symbol with “?” indicates an individual who did not have clinical evaluation and genetic testing; squares indicate males; circles indicate females; shaded symbol indicates an individual who was not included in the LOD score calculations. The proband patient in each family is marked with an arrow. The right part of each panel indicates direct sequencing data of NEXN mutant sequences compared with a normal control. (A) Pedigree of Family A. NEXN mutation p.Q131E was identified in II-2, II-3, and III-1. (B) Pedigree of Family B. NEXN mutation p.R279C was identified in II-1, III-2, III-4, and IV-1. The American Journal of Human Genetics 2010 87, 687-693DOI: (10.1016/j.ajhg.2010.10.002) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Location and Conservation of the NEXN Protein Amino Acid Residues Affected by the Mutations NEXN is a 13-exon gene encoding two N-terminally located actin-binding domains (ABD), a coiled-coil domain (CC), and a C-terminal immunoglobulin superfamily class (IGcam). (A) Schematic structure of NEXN mRNA and protein. The p.Q131E mutation is located in exon 5 and in the first actin-binding domain; the p.R279C mutation is located in exon 8 and in the coiled-coil domain. (B) NEXN peptide sequences surrounding the mutated residues (black box) with multiple interspecies alignments generated by ClustalW. Q131 and R279 amino acid residues of NEXN are highly conserved across species. The American Journal of Human Genetics 2010 87, 687-693DOI: (10.1016/j.ajhg.2010.10.002) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Distribution of V5-Tagged NEXN in C2C12 Cells C2C12 cells transfected with V5-tagged full-length wild-type (WT) (A–C) or mutants p.Q131E (D–F) and p.R279C (G–I) or with V5-tagged first actin-binding domain (ABD) (J–L) or mutant NEXNABD-p.Q131E (M–O). NEXN constructs were fixed 24 hr after the transfection and stained by a V5 antibody followed by a secondary antibody (A, D, G, J, M) and incubated with phalloidin and DAPI (B, E, H, K, N) (Magnification: 400×). Merged images (C, F, I, L, O) are shown. Overexpression of wild-type NEXN was preferentially distributed along F-actin, whereas mutants p.Q131E and p.R279C showed partially abnormal aggregates in the cytoplasm. Expression of the NEXNABD fragment of amino acids 1–164 in C2C12 cells showed that this fragment tended to be localized in the nucleus and was partially distributed along F-actin, whereas the mutant NEXNABD-p.Q131E fragment was completely dispersed into the nucleus and cytoplasm. The American Journal of Human Genetics 2010 87, 687-693DOI: (10.1016/j.ajhg.2010.10.002) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Binding of NEXN to α-Actin Binding of the full-length NEXN and NEXN fragment to α-actin was analyzed by coimmunoprecipitation and subsequent immunoblotting. Lysates from HEK293 cells cotransfected with NT-GFP-tagged α-actin and V5-tagged NEXN constructs (NEXN, NEXN-p.Q131E, NEXN-p.R279C, NEXNABD, or NEXNABD-p.Q131E) were immunoprecipitated with a V5-specific antibody (IP: V5) and subsequently immunoblotted with a HRP-conjugated V5- and GFP-specific antibody. Untransfected cells served as negative controls. Inputs were cell lysates subject to immunoblotting without immunoprecipitation. The American Journal of Human Genetics 2010 87, 687-693DOI: (10.1016/j.ajhg.2010.10.002) Copyright © 2010 The American Society of Human Genetics Terms and Conditions