title: New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations.
abstract: Protein aggregate myopathies (PAMs) define muscle disorders characterized by protein accumulation in muscle fibres. We describe a new PAM in a patient with proximal muscle weakness and hypertrophic cardiomyopathy, whose muscle fibres contained inclusions containing myosin and myosin-associated proteins, and aberrant distribution of microtubules. These lesions appear as intact A- and M-bands lacking thin filaments and Z-discs. These features differ from inclusions in myosin storage myopathy (MSM), but are highly similar to those in mice deficient for the muscle-specific RING finger proteins MuRF1 and MuRF3. Sanger sequencing excluded mutations in the MSM-associated gene MYH7 but identified mutations in TRIM63 and TRIM54, encoding MuRF1 and MuRF3, respectively. No mutations in other potentially disease-causing genes were identified by Sanger and whole exome sequencing. Analysis of seven family members revealed that both mutations segregated in the family but only the homozygous TRIM63 null mutation in combination with the heterozygous TRIM54 mutation found in the proband caused the disease phenotype. Both MuRFs are microtubule-associated proteins localizing to sarcomeric M-bands and Z-discs. They are E3 ubiquitin ligases that play a role in degradation of sarcomeric proteins, stabilization of microtubules and myogenesis. Lack of ubiquitin and the 20S proteasome subunit in the inclusions found in the patient suggested impaired turnover of thick filament proteins. Disruption of microtubules in cultured myotubes was rescued by transient expression of wild-type MuRF1. The unique features of this novel myopathy point to defects in homeostasis of A-band proteins in combination with instability of microtubules as cause of the disease.
authors: Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology, CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Barcelona, Spain.
authors: Montse
authors: M
authors: Olivé
authors: Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg SE-413 45, Sweden.
authors: Saba
authors: S
authors: Abdul-Hussein
authors: Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg SE-413 45, Sweden.
authors: Anders
authors: A
authors: Oldfors
authors: Department of Cardiology.
authors: José
authors: J
authors: González-Costello
authors: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, D-53121 Bonn, Germany.
authors: Peter F M
authors: PF
authors: van der Ven
authors: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, D-53121 Bonn, Germany.
authors: Dieter O
authors: DO
authors: Fürst
authors: Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology.
authors: Laura
authors: L
authors: González
authors: Institute of Neuropathology, Department of Pathology and.
authors: Dolores
authors: D
authors: Moreno
authors: Scientific and Technical Services Facility, Biology Unit, CCiTUB, IDIBELL-University of Barcelona, Barcelona, Spain.
authors: Benjamín
authors: B
authors: Torrejón-Escribano
authors: Department of Cardiology.
authors: Josefina
authors: J
authors: Alió
authors: Department of Neurology, Hospital del Mar, Barcelona, Spain.
authors: Adolf
authors: A
authors: Pou
authors: CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Barcelona, Spain, Institute of Neuropathology, Department of Pathology and.
authors: Isidro
authors: I
authors: Ferrer
authors: Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg SE-413 45, Sweden, Department of Clinical and Medical Genetics, University of Gothenburg, Gothenburg SE-405 30, Sweden and Systems Biology Research Centre, School of Biomedicine, University of Skövde, Skövde SE-541 28, Sweden homa.tajsharghi@gu.se.
authors: Homa
authors: H
authors: Tajsharghi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D032342:Muscle Cells / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D018908:Muscle Weakness / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000378:metabolism; D013030:Spain; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D066329:Protein Aggregates; C413644:Rnf30 protein, mouse; C485888:TRIM54 protein, human; D000070584:Tripartite Motif Proteins; C440908:TRIM63 protein, human; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases