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.

Abnormal spontaneous activity in primary myopathic disorders

“…In both of these reports, the patients were quite heterogeneous, with various molecular abnormalities . The absence of MDs may be characteristic for specific types of mutations in our group of patients with desminopathy, which was very homogeneous, and derived from 3 families with 2 mutations in the desmin gene (a novel missense mutation, Q348P, and a small deletion of 9 nucleotides, A357_E359del), as described earlier . An alternative explanation is that desminopathy, in general, demonstrates pathologic alterations that tend to be less severe and more homogeneous when compared with other subtypes of MFM …”

Association of Desmin Gene Variant rs1058261 with Cardiovascular Disease, the TAMRISK Study

“…Previously, the C allele of the benign DES rs1058261 was associated with myofibrillar myopathies in two Polish families having other pathological mutations in the DES gene (Fichna et al 2014). It is thought that intimal smooth muscle cells (SMCs) in native atherosclerotic plaque derive mainly from the medial arterial layer.…”

“…DNA was extracted from buccal swabs using a commercial kit (Qiagen Inc., Valencia, Calif., USA). An intragenic SNP at nucleotide position 828 (rs1058261) of the desmin gene was chosen (Fichna et al 2014). For DNA genotyping, PCR was performed in a final volume of 5 µl containing 10 ng of sample DNA, 0.05 µl of custom SNP-specific Assay mix and 2.18 µl of Taqman Universal PCR Master Mix.…”

“…Desmin (DES) is a muscle-specific intermediate filament (IF) protein that connects cell organelles by forming a cytoskeletal network. It is expressed in skeletal, cardiac and smooth muscle cells (SMC) (Raguz et al 1998, Fichna et al 2014. Desmin is a useful marker for SMC differentiation (Nikkari et al 1988).…”

“…Since the recognition of the involvement of the DES gene in human disease in 1998 (Goldfarb et al 1998), the number of publications on different DES mutations and associated phenotypes has increased steadily (van Spaendonck-Zwarts et al 2011). We wanted to study whether a common intragenic single nucleotide polymorphism (SNP) at nucleotide position 828 (rs1058261) of the DES gene (Fichna et al 2014) associates with hypertension, cerebrovascular complications and all combined cardiovascular events in a Finnish population from the Tampere adult population cardiovascular risk study (TAMRISK).…”