TY  - JOUR
A1  - Winter, Lilli
A1  - Türk, Matthias
A1  - Harter, Patrick Nikolaus
A1  - Mittelbronn, Michel Guy André
A1  - Kornblum, Cornelia
A1  - Norwood, Fiona
A1  - Jungbluth, Heinz
A1  - Thiel, Christian
A1  - Schlötzer-Schrehardt, Ursula
A1  - Schröder, Rolf
T1  - Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy
T2  - Acta Neuropathologica Communications
N2  - Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients.
PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount.
Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology.
KW  - Plectin
KW  - Epidermolysis bullosa simplex with muscular dystrophy
KW  - Skeletal muscle
KW  - Intermediate filaments
KW  - Mitochondria
KW  - Desmin
KW  - Protein aggregates
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/44704
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-447044
SN  - 2051-5960
N1  - © 2016 Winter et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
VL  - 44
IS  - 1, Art. 44
SP  - 1
EP  - 10
PB  - Biomed Central
CY  - London
ER  -