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Histopathology. 2016 Oct;69(4):542-50. doi: 10.1111/his.12963. Epub 2016 May 12.

Phospholamban p.Arg14del cardiomyopathy is characterized by phospholamban aggregates, aggresomes, and autophagic degradation.

Author information

1
Department of Cardiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
2
Department of Pathology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
3
Interuniversity Cardiology Institute of The Netherlands (ICIN), Utrecht, the Netherlands.
4
Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
5
Department of Pathology, University Medical Centre Utrecht, Utrecht, the Netherlands.
6
Department of Pathology, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands.
7
Department of Pathology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands. a.j.h.suurmeijer@umcg.nl.

Abstract

AIMS:

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.

METHODS AND 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.

KEYWORDS:

arrhythmogenic cardiomyopathy; autophagy; dilated cardiomyopathy; immunohistochemistry; phospholamban; protein aggregation

PMID:
26970417
DOI:
10.1111/his.12963
[Indexed for MEDLINE]

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