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New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations

Journal article
Authors M. Olive
Saba Abdul-Hussein
Anders Oldfors
J. Gonzalez-Costello
P. F. M. van der Ven
D. O. Furst
L. Gonzalez
D. Moreno
B. Torrejon-Escribano
J. Alio
A. Pou
I. Ferrer
Homa Tajsharghi
Published in Human Molecular Genetics
Volume 24
Issue 13
Pages 3638-3650
ISSN 0964-6906
Publication year 2015
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Institute of Biomedicine, Department of Pathology
Pages 3638-3650
Language en
Links dx.doi.org/10.1093/hmg/ddv108
Keywords HUMAN HYPERTROPHIC CARDIOMYOPATHY, MYOSIN STORAGE MYOPATHY, MUSCLE RING, FINGER-1, IN-VIVO, MYOFIBRILLAR MYOPATHIES, MECHANISMS, ATROPHY, GENE, DIFFERENTIATION, UBIQUITINATION, Biochemistry & Molecular Biology, Genetics & Heredity
Subject categories Biochemistry and Molecular Biology

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.

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