Back to Search Start Over

Two Desmin Gene Mutations Associated with Myofibrillar Myopathies in Polish Families.

Authors :
Fichna, Jakub Piotr
Karolczak, Justyna
Potulska-Chromik, Anna
Miszta, Przemyslaw
Berdynski, Mariusz
Sikorska, Agata
Filipek, Slawomir
Redowicz, Maria Jolanta
Kaminska, Anna
Zekanowski, Cezary
Source :
PLoS ONE. Dec2014, Vol. 9 Issue 12, p1-22. 22p.
Publication Year :
2014

Abstract

Desmin is a muscle-specific intermediate filament protein which forms a network connecting the sarcomere, T tubules, sarcolemma, nuclear membrane, mitochondria and other organelles. Mutations in the gene coding for desmin (DES) cause skeletal myopathies often combined with cardiomyopathy, or isolated cardiomyopathies. The molecular pathomechanisms of the disease remain ambiguous. Here, we describe and comprehensively characterize two DES mutations found in Polish patients with a clinical diagnosis of desminopathy. The study group comprised 16 individuals representing three families. Two mutations were identified: a novel missense mutation (Q348P) and a small deletion of nine nucleotides (A357_E359del), previously described by us in the Polish population. A common ancestry of all the families bearing the A357_E359del mutation was confirmed. Both mutations were predicted to be pathogenic using a bioinformatics approach, including molecular dynamics simulations which helped to rationalize abnormal behavior at molecular level. To test the impact of the mutations on DES expression and the intracellular distribution of desmin muscle biopsies were investigated. Elevated desmin levels as well as its atypical localization in muscle fibers were observed. Additional staining for M-cadherin, α-actinin, and myosin heavy chains confirmed severe disruption of myofibrill organization. The abnormalities were more prominent in the Q348P muscle, where both small atrophic fibers as well large fibers with centrally localized nuclei were observed. We propose that the mutations affect desmin structure and cause its aberrant folding and subsequent aggregation, triggering disruption of myofibrils organization. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
19326203
Volume :
9
Issue :
12
Database :
Academic Search Index
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
100187405
Full Text :
https://doi.org/10.1371/journal.pone.0115470