PLEC1 Mutations Underlie Adult-Onset Dilated Cardiomyopathy in Epidermolysis Bullosa Simplex with Muscular Dystrophy Maria C. Bolling, Hendri H. Pas,

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PLEC1 Mutations Underlie Adult-Onset Dilated Cardiomyopathy in Epidermolysis Bullosa Simplex with Muscular Dystrophy Maria C. Bolling, Hendri H. Pas, Marianne de Visser, Eleonora Aronica, Ellen G. Pfendner, Maarten P. van den Berg, Gilles F.H. Diercks, Albert J.H. Suurmeijer, Marcel F. Jonkman Journal of Investigative Dermatology Volume 130, Issue 4, Pages 1178-1181 (April 2010) DOI: 10.1038/jid.2009.390 Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Compound heterozygous PLEC1 mutations in epidermolysis bullosa simplex-muscular dystrophy (EBS-MD) with dilated cardiomyopathy (DCM). DNA mutation analysis revealed compound heterozygous PLEC1 mutations in the proband and his affected sister. (a) On the paternal allele, a heterozygous c.1019G>A substitution was found, changing a highly conserved arginine (CGA) into a glutamine (CAA) at residue 323 in the plectin protein, Arg323Gln (GenBank NM_000445.2). (b) On the maternal allele, a heterozygous c.4891G>T substitution was detected changing a glutamic acid (Glu) into a premature termination codon (X) at residue 1614, Glu1614X (GenBank NM_000445.2). (c) Schematic representation of the plectin protein, with the mutations found in this study depicted in red boxes. The nonsense mutation Glu1614X is located in the rod domain, whereas the missense mutation resides in the first α-helical spectrin repeat segment of plectin, adjacent to the actin-binding domain (ABD). Journal of Investigative Dermatology 2010 130, 1178-1181DOI: (10.1038/jid.2009.390) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Aberrant staining patterns of plectin and its binding partners in the skin, skeletal muscle, and myocardium of the proband. (a) Immunofluorescence microscopy of nonlesional skin of the proband (right panels) showed slightly diminished plectin (5B3) staining along the basement membrane zone (BMZ) and absent staining of intercellular substance (arrow in control) in the basal layers. Stainings for BP180 (1D1) and BP230 (R815), along BMZ, were reduced. (b) Subsarcolemmal and cytoplasmic desmin aggregations (arrows) are seen in a skeletal muscle biopsy of the proband (right panels). As described by McMillan et al. (2007), in cross-sections of normal skeletal muscle, plectin 10F6 staining shows a checkerboard-like distribution with cytoplasmic and sarcolemmal (closed arrowheads) staining of type II fibers and only sarcolemmal staining in type I fibers, contrary to the hemidesmosome (HD)121 staining as described by Schroder et al. (1997). In the proband, 10F6 staining was preserved. Type II fibers were small and few in number (arrow). Note the cytoplasmatic nuclei, the variable diameter of muscle fibers, and the widened interfiber spaces as signs of muscular dystrophy. (c) Immunofluorescence staining for desmoplakin on myocardial tissue of the proband (right panels) showed widened intercalated discs (IDs) (arrow) with a more cytoplasmatic position of desmoplakin. Desmin staining at IDs (arrows) was retracted to a more cytoplasmic position and Z-disc staining (open arrowhead) was disrupted. In proband myocardium, plectin (10F6) staining showed depletion at IDs and abnormal aggregates (closed arrowheads). Scale bar=50μm. Journal of Investigative Dermatology 2010 130, 1178-1181DOI: (10.1038/jid.2009.390) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions