Distinct distal myopathy phenotype caused by VCP gene mutation in a Finnish family
ABSTRACT Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. We report a new distal phenotype caused by VCP gene mutation in a Finnish family with nine affected members in three generations. Patients had onset of distal leg muscle weakness and atrophy in the anterior compartment muscles after age 35, which caused a foot drop at age 50. None of the siblings had scapular winging, proximal myopathy, cardiomyopathy or respiratory problems during long-term follow-up. Three distal myopathy patients developed rapidly progressive dementia, became bedridden and died of cachexia and pneumonia and VCP gene mutation P137L (c.410C>T) was then identified in the family. Late onset autosomal dominant distal myopathy with rimmed vacuolar muscle pathology was not sufficient for exact diagnosis in this family until late-occurring dementia provided the clue for molecular diagnosis. VCP needs to be considered in the differential diagnostic work-up in patients with distal myopathy phenotype.
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- "A key component of the ERAD pathway is VCP which, among others, retro-translocates unfolded proteins from the ER into the cytosol for degradation by the UPS . Primary mutations in VCP cause a muscle disease with rimmed vacuolar pathology , . VCP has also been reported to regulate ubiquitin-containing autophagosome maturation during myopathic proteomic stress , , and may therefore be involved in autophagosomal activation in TMD muscle. "
ABSTRACT: Tibial muscular dystrophy (TMD) is a late onset, autosomal dominant distal myopathy that results from mutations in the two last domains of titin. The cascade of molecular events leading from the causative Titin mutations to the preterm death of muscle cells in TMD is largely unknown. In this study we examined the mRNA and protein changes associated with the myopathology of TMD. To identify these components we performed gene expression profiling using muscle biopsies from TMD patients and healthy controls. The profiling results were confirmed through quantitative real-time PCR and protein level analysis. One of the pathways identified was activation of endoplasmic reticulum (ER) stress response. ER stress activates the unfolded protein response (UPR) pathway. UPR activation was supported by elevation of the marker genes HSPA5, ERN1 and the UPR specific XBP1 splice form. However, UPR activation appears to be insufficient to correct the protein abnormalities causing its activation because degenerative TMD muscle fibres show an increase in ubiquitinated protein inclusions. Abnormalities of VCP-associated degradation pathways are also suggested by the presence of proteolytic VCP fragments in western blotting, and VCP's accumulation within rimmed vacuoles in TMD muscle fibres together with p62 and LC3B positive autophagosomes. Thus, pathways controlling turnover and degradation, including autophagy, are distorted and lead to degeneration and loss of muscle fibres.PLoS ONE 03/2014; 9(3):e90819. DOI:10.1371/journal.pone.0090819 · 3.23 Impact Factor
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ABSTRACT: Distal myopathies are a group of muscle diseases which share the clinical pattern of predominant weakness in the feet and/or hands. Rapid advance in the understanding of underlying gene defects have to date separated more than 20 distinct disorders and many are yet without genetic characterisation. No definite diagnosis can be made on other grounds than identification of the final molecular genetic defect. Besides usual investigations including EMG and muscle biopsy, muscle imaging is very important in defining the precise pattern of muscle involvement. Based on the combination of age at onset, mode of inheritance, pathology and muscle imaging, the number of underlying candidate genes for a certain disease can be significantly reduced, which is of help for the molecular genetic approach.Neuromuscular Disorders 12/2011; 22(1):5-12. DOI:10.1016/j.nmd.2011.10.003 · 3.13 Impact Factor
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ABSTRACT: To identify the causative gene in an autosomal dominant limb-girdle muscular dystrophy (LGMD) with skeletal muscle vacuoles. Exome sequencing was used to identify candidate mutations in the studied pedigree. Genome-wide linkage was then used to narrow the list of candidates to a single disease-associated mutation. Additional pedigrees with dominant or sporadic myopathy were screened for mutations in the same gene (DNAJB6) using exome sequencing. Skeletal muscle from affected patients was evaluated with histochemistry and immunohistochemical stains for dystrophy-related proteins, SMI-31, TDP43, and DNAJB6. Exome analysis in 3 affected individuals from a family with dominant LGMD and vacuolar pathology identified novel candidate mutations in 22 genes. Linkage analysis excluded all variants except a Phe93Leu mutation in the G/F domain of the DNAJB6 gene, which resides within the LGMD locus at 7q36. Analysis of exome sequencing data from other pedigrees with dominant myopathy identified a second G/F domain mutation (Pro96Arg) in DNAJB6. Affected muscle showed mild dystrophic changes, vacuoles, and abnormal aggregation of proteins, including TDP-43 and DNAJB6 itself. Mutations within the G/F domain of DNAJB6 are a novel cause of dominantly-inherited myopathy. DNAJB6 is a member of the HSP40/DNAJ family of molecular co-chaperones tasked with protecting client proteins from irreversible aggregation during protein synthesis or during times of cellular stress. The abnormal accumulation of several proteins in patient muscle, including DNAJB6 itself, suggest that DNAJB6 function is compromised by the identified G/F domain mutations.Annals of Neurology 04/2012; 71(3):407-16. DOI:10.1002/ana.22683 · 11.91 Impact Factor