title: Phospholamban p.Arg14del cardiomyopathy is characterized by phospholamban aggregates, aggresomes, and autophagic degradation.
abstract: OBJECTIVE
  The non-desmosomal phospholamban PLN p.Arg14del mutation was identified in patients diagnosed with dilated cardiomyopathy (DCM) and/or arrhythmogenic cardiomyopathy (ACM). We aimed to investigate whether this mutation leads to aggregation, aggresome formation and autophagy of mutant PLN protein.
  
  
  RESULTS
  We studied 20 complete heart specimens of PLN p.Arg14del mutation carriers [mean age 48 ± 15 years; 55% males], either from autopsies or from explants. Gross and microscopic examination showed biventricular cardiomyopathy with histopathological features of both ACM and DCM, i.e. a combination of fibrofatty replacement and interstitial fibrosis. Immunohistochemistry for PLN showed large perinuclear PLN protein aggregates in cardiomyocytes in both ventricles in all examined hearts. The median numbers of PLN-containing aggregates were 12 per 5 mm(2) range 3-48 mm2 in right ventricular myocardium and 13 per 5 mm(2) (range 5-89 mm(2) ) in left ventricular myocardium. Double immunohistochemical staining showed colocalization of autophagy markers p62 (sequestosome-1) and microtubule-associated protein light chain 3 with PLN in all aggregates, suggestive of degradation by selective autophagy. On electron microscopy, the ultrastructural appearance of these PLN-containing aggregates was typical of aggresomes; they were not surrounded by a membrane, and were located adjacent to the microtubular organizing centre. PLN-containing aggregates were not found in 10 PLN-negative cases of idiopathic and genetic DCM or in seven cases of desmosomal ACM.
  
  
  CONCLUSIONS
  PLN p.Arg14del cardiomyopathy is a biventricular cardiomyopathy characterized by large perinuclear PLN protein aggregates with a typical ultrastructural appearance of aggresomes. PLN detected by immunohistochemistry appears to be a sensitive and specific marker for this disease.
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.|Department of Pathology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.|Interuniversity Cardiology Institute of The Netherlands (ICIN), Utrecht, the Netherlands.
authors.forename: Wouter P
authors.identifier: http://orcid.org/0000-0003-4852-9379
authors.initials: WP
authors.lastname: Te Rijdt
authors.affiliation: Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.affiliation: Department of Pathology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Aryan
authors.initials: A
authors.lastname: Vink
authors.affiliation: Department of Pathology, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Allard C
authors.initials: AC
authors.lastname: van der Wal
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Maarten P
authors.initials: MP
authors.lastname: van den Berg
authors.affiliation: Department of Pathology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands. a.j.h.suurmeijer@umcg.nl.
authors.forename: Albert J H
authors.initials: AJ
authors.lastname: Suurmeijer
mesh_terms: D001343:Autophagy; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D000099211:Phospholamban
keywords: arrhythmogenic cardiomyopathy; autophagy; dilated cardiomyopathy; immunohistochemistry; phospholamban; protein aggregation