title: Two desmin gene mutations associated with myofibrillar myopathies in Polish families.
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.
authors.affiliation: Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland.
authors.forename: Jakub Piotr
authors.initials: JP
authors.lastname: Fichna
authors.affiliation: Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Karolczak
authors.affiliation: Department of Neurology, Medical University of Warsaw, Warszawa, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Potulska-Chromik
authors.affiliation: Faculty of Chemistry and Biological and Chemical Research Centre, University of Warsaw, Warszawa, Poland.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Miszta
authors.affiliation: Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Berdynski
authors.affiliation: Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Sikorska
authors.affiliation: Faculty of Chemistry and Biological and Chemical Research Centre, University of Warsaw, Warszawa, Poland.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Filipek
authors.affiliation: Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland.
authors.forename: Maria Jolanta
authors.initials: MJ
authors.lastname: Redowicz
authors.affiliation: Department of Neurology, Medical University of Warsaw, Warszawa, Poland; Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kaminska
authors.affiliation: Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Zekanowski
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D003893:Desmin / Q000737:chemistry* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D056004:Molecular Dynamics Simulation; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D011044:Poland; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D003893:Desmin