-
Internal Medicine (Tokyo, Japan) May 2022Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and is considered quite rare. Respiratory insufficiency can be...
Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and is considered quite rare. Respiratory insufficiency can be the sole symptom in the disease course. We herein report the first Japanese HMERF patient with a p.P31732L mutation in titin. The patient manifested respiratory failure and mild weakness of the neck flexor muscle at 69 years old and showed fatty replacement of the bilateral semitendinosus muscles on muscle imaging. Our case indicates that HMERF with a heterozygous p.P31732L mutation should be included in the differential diagnosis of muscular diseases presenting with early respiratory failure.
Topics: Aged; Connectin; Genetic Diseases, Inborn; Humans; Japan; Muscle, Skeletal; Muscular Diseases; Mutation; Respiratory Insufficiency
PubMed: 34670883
DOI: 10.2169/internalmedicine.7733-21 -
Muscle & Nerve Dec 2021Immune-mediated necrotizing myopathy (IMNM) is an immune-mediated myopathy typically presenting with progressive subacute weakness and characteristic, but nonspecific,...
INTRODUCTION/AIMS
Immune-mediated necrotizing myopathy (IMNM) is an immune-mediated myopathy typically presenting with progressive subacute weakness and characteristic, but nonspecific, myopathological findings. Atypical cases however can mimic other inherited or acquired myopathies, depriving patients of treatment. We describe a cohort of such patients.
METHODS
We retrospectively identified IMNM patients who either previously carried a diagnosis of an inherited myopathy established on clinicopathological grounds or whose muscle biopsies displayed atypical features suggestive of a different myopathy.
RESULTS
Among 131 IMNM patients, seven previously unreported patients (5%) met one of the above criteria. Three patients were diagnosed with limb-girdle muscular dystrophy on the basis of a chronic progressive course of weakness and family history of myopathy or cardiomyopathy. The other four patients displayed atypical histological features (two prominent mitochondrial abnormalities, one myofibrillar pathology, and one granulomatous inflammation). Immunostaining of biopsies from 12 additional IMNM patients did not identify myofibrillar pathology. The patient with granulomatous inflammation was known to have pulmonary sarcoidosis. Genetic testing for inherited myopathies was unrevealing. Antibodies against 3-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle were identified in 5 and 1 patients, respectively. Four patients presented with slowly progressive weakness over 3-13 y, while weakness was subacute over ≤6 mo in three patients. All patients responded to immunomodulatory therapy.
DISCUSSION
Atypical clinical and histological features can occur in IMNM patients, causing delays in diagnosis and treatment. Clinicians should, therefore, consider IMNM in the differential diagnosis of unexplained proximal myopathies in spite of atypical clinical and myopathological findings.
Topics: Autoantibodies; Autoimmune Diseases; Humans; Muscle, Skeletal; Muscular Diseases; Myositis; Necrosis; Retrospective Studies
PubMed: 34617293
DOI: 10.1002/mus.27435 -
Heart Failure Reviews Jul 2022Cardiomyopathy affects approximately 1 in 500 adults and is the leading cause of death. Familial cases are common, and mutations in many genes are involved in... (Review)
Review
Cardiomyopathy affects approximately 1 in 500 adults and is the leading cause of death. Familial cases are common, and mutations in many genes are involved in cardiomyopathy, especially those in genes encoding cytoskeletal, sarcomere, and nuclear envelope proteins. Filamin C is an actin-binding protein encoded by filamin C (FLNC) gene and participates in sarcomere stability maintenance. FLNC was first demonstrated to be a causal gene of myofibrillar myopathy; recently, it has been found that FLNC mutation plays a critical role in the pathogenesis of cardiomyopathy. In this review, we summarized the physiological roles of filamin C in cardiomyocytes and the genetic evidence for links between FLNC mutations and cardiomyopathies. Truncated FLNC is enriched in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Non-truncated FLNC is enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy. Two major pathomechanisms in FLNC-related cardiomyopathy have been described: protein aggregation resulting from non-truncating mutations and haploinsufficiency triggered by filamin C truncation. Therefore, it is important to understand the cellular biology and molecular regulation of FLNC to design new therapies to treat patients with FLNC-related cardiomyopathy.
Topics: Cardiomyopathies; DNA; Filamins; Humans; Mutation; Myopathies, Structural, Congenital
PubMed: 34535832
DOI: 10.1007/s10741-021-10172-z -
Neurology. Genetics Jun 2021To determine whether a new indel mutation in the dimerization domain of filamin C (FLNc) causes a hereditary myopathy with protein aggregation in muscle fibers, we...
OBJECTIVE
To determine whether a new indel mutation in the dimerization domain of filamin C (FLNc) causes a hereditary myopathy with protein aggregation in muscle fibers, we clinically and molecularly studied a German family with autosomal dominant myofibrillar myopathy (MFM).
METHODS
We performed mutational analysis in 3 generations, muscle histopathology, and proteomic studies of IM protein aggregates. Functional consequences of the mutation were investigated with interaction and transfection studies and biophysics molecular analysis.
RESULTS
Eight patients revealed clinical features of slowly progressive proximal weakness associated with a heterozygous c.8025_8030delCAAGACinsA (p.K2676Pfs*3) mutation in . Two patients exhibited a mild cardiomyopathy. MRI of skeletal muscle revealed lipomatous changes typical for MFM with mutations. Muscle biopsies showed characteristic MFM findings with protein aggregation and lesion formation. The proteomic profile of aggregates was specific for MFM-filaminopathy and indicated activation of the ubiquitin-proteasome system (UPS) and autophagic pathways. Functional studies revealed that mutant FLNc is misfolded, unstable, and incapable of forming homodimers and heterodimers with wild-type FLNc.
CONCLUSIONS
This new MFM-filaminopathy family confirms that expression of mutant leads to an adult-onset muscle phenotype with intracellular protein accumulation. Mutant FLNc protein is biochemically compromised and leads to dysregulation of protein quality control mechanisms. Proteomic analysis of MFM protein aggregates is a potent method to identify disease-relevant proteins, differentiate MFM subtypes, evaluate the relevance of gene variants, and identify novel MFM candidate genes.
PubMed: 34235269
DOI: 10.1212/NXG.0000000000000590 -
BMC Genomics Jun 2021Myofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle. In horses, myofibrillar myopathy is a late-onset disease of...
Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy.
BACKGROUND
Myofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle. In horses, myofibrillar myopathy is a late-onset disease of unknown origin characterized by poor performance, atrophy, myofibrillar disarray, and desmin aggregation in skeletal muscle. This study evaluated molecular and ultrastructural signatures of myofibrillar myopathy in Warmblood horses through gluteal muscle tandem-mass-tag quantitative proteomics (5 affected, 4 control), mRNA-sequencing (8 affected, 8 control), amalgamated gene ontology analyses, and immunofluorescent and electron microscopy.
RESULTS
We identified 93/1533 proteins and 47/27,690 genes that were significantly differentially expressed. The top significantly differentially expressed protein CSRP3 and three other differentially expressed proteins, including, PDLIM3, SYNPO2, and SYNPOL2, are integrally involved in Z-disc signaling, gene transcription and subsequently sarcomere integrity. Through immunofluorescent staining, both desmin aggregates and CSRP3 were localized to type 2A fibers. The highest differentially expressed gene CHAC1, whose protein product degrades glutathione, is associated with oxidative stress and apoptosis. Amalgamated transcriptomic and proteomic gene ontology analyses identified 3 enriched cellular locations; the sarcomere (Z-disc & I-band), mitochondrial complex I and the extracellular matrix which corresponded to ultrastructural Z-disc disruption and mitochondrial cristae alterations found with electron microscopy.
CONCLUSIONS
A combined proteomic and transcriptomic analysis highlighted three enriched cellular locations that correspond with MFM ultrastructural pathology in Warmblood horses. Aberrant Z-disc mechano-signaling, impaired Z-disc stability, decreased mitochondrial complex I expression, and a pro-oxidative cellular environment are hypothesized to contribute to the development of myofibrillar myopathy in Warmblood horses. These molecular signatures may provide further insight into diagnostic biomarkers, treatments, and the underlying pathophysiology of MFM.
Topics: Animals; Extracellular Matrix; Horses; Muscle, Skeletal; Myopathies, Structural, Congenital; Proteomics; Sarcomeres; Transcriptome
PubMed: 34112090
DOI: 10.1186/s12864-021-07758-0 -
Neurology. Genetics Jun 2021
PubMed: 34084941
DOI: 10.1212/NXG.0000000000000587 -
Journal of Integrative Neuroscience Mar 2021Infantile hypertonic myofibrillar myopathy is characterized by the rapid development of rigid muscles and respiratory insufficiency soon after birth, with very high...
Infantile hypertonic myofibrillar myopathy is characterized by the rapid development of rigid muscles and respiratory insufficiency soon after birth, with very high mortality. It is extremely rare, and only a few cases having been reported until now. Here we report four Chinese infants with fatal neuromuscular disorders characterized by abdominal and trunk skeletal muscle stiffness and rapid respiratory insufficiency progression. Electromyograms showed increased insertion activities and profuse fibrillation potentials with complex repetitive discharges. Immunohistochemistry staining of muscle biopsies showed accumulations of desmin in the myocytes. Powdery Z-bands with dense granules across sarcomeres were observed in muscle fibers using electron microscopy. All patients carry a homozygous c.3G>A mutation in the gene, which resulted in the loss of the initiating methionine and the absence of protein. This study's findings help further understand the disease and highlight a founder mutation in the Chinese population.
Topics: China; Electromyography; Fatal Outcome; Humans; Infant; Magnetic Resonance Imaging; Male; Muscle, Skeletal; Myopathies, Structural, Congenital; alpha-Crystallin B Chain
PubMed: 33834702
DOI: 10.31083/j.jin.2021.01.267 -
Communications Biology Mar 2021Mechanical stress induced by contractions constantly threatens the integrity of muscle Z-disc, a crucial force-bearing structure in striated muscle. The PDZ-LIM proteins...
Mechanical stress induced by contractions constantly threatens the integrity of muscle Z-disc, a crucial force-bearing structure in striated muscle. The PDZ-LIM proteins have been proposed to function as adaptors in transducing mechanical signals to preserve the Z-disc structure, however the underlying mechanisms remain poorly understood. Here, we show that LDB3, a well-characterized striated muscle PDZ-LIM protein, modulates mechanical stress signaling through interactions with the mechanosensing domain in filamin C, its chaperone HSPA8, and PKCα in the Z-disc of skeletal muscle. Studies of Ldb3 mice indicate that the myopathy-associated LDB3 p.Ala165Val mutation triggers early aggregation of filamin C and its chaperones at muscle Z-disc before aggregation of the mutant protein. The mutation causes protein aggregation and eventually Z-disc myofibrillar disruption by impairing PKCα and TSC2-mTOR, two important signaling pathways regulating protein stability and disposal of damaged cytoskeletal components at a major mechanosensor hub in the Z-disc of skeletal muscle.
Topics: Adaptor Proteins, Signal Transducing; Animals; Autophagy; Disease Models, Animal; Down-Regulation; Filamins; HSC70 Heat-Shock Proteins; LIM Domain Proteins; Mechanotransduction, Cellular; Mice, Inbred C57BL; Mice, Transgenic; Muscle Contraction; Muscle Strength; Muscle, Skeletal; Myopathies, Structural, Congenital; Point Mutation; Protein Aggregates; Protein Aggregation, Pathological; Protein Kinase C-alpha; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein; Mice
PubMed: 33742095
DOI: 10.1038/s42003-021-01864-1 -
Journal of Muscle Research and Cell... Jun 2021Hypertrophic cardiomyopathy (HCM) often leads to heart failure. Mutations in sarcomeric proteins are most frequently the cause of HCM but in many patients the gene...
Hypertrophic cardiomyopathy (HCM) often leads to heart failure. Mutations in sarcomeric proteins are most frequently the cause of HCM but in many patients the gene defect is not known. Here we report on a young man who was diagnosed with HCM shortly after birth. Whole exome sequencing revealed a mutation in the FLNC gene (c.7289C > T; p.Ala2430Val) that was previously shown to cause aggregation of the mutant protein in transfected cells. Myocardial tissue from patients with this mutation has not been analyzed before and thus, the underlying etiology is not well understood. Myocardial tissue of our patient obtained during myectomy at the age of 23 years was analyzed in detail by histochemistry, immunofluorescence staining, electron microscopy and western blot analysis. Cardiac histology showed a pathology typical for myofibrillar myopathy with myofibril disarray and abnormal protein aggregates containing BAG3, desmin, HSPB5 and filamin C. Analysis of sarcomeric and intercalated disc proteins showed focally reduced expression of the gap junction protein connexin43 and Xin-positive sarcomeric lesions in the cardiomyocytes of our patient. In addition, autophagy pathways were altered with upregulation of LC3-II, WIPI1 and HSPB5, 6, 7 and 8. We conclude that the p.Ala2430Val mutation in FLNC most probably is associated with HCM characterized by abnormal intercalated discs, disarray of myofibrils and aggregates containing Z-disc proteins similar to myofibrillar myopathy, which supports the pathological effect of the mutation.
Topics: Adaptor Proteins, Signal Transducing; Adult; Apoptosis Regulatory Proteins; Cardiomyopathy, Hypertrophic; Filamins; Humans; Male; Mutation; Myocytes, Cardiac; Myopathies, Structural, Congenital; Young Adult
PubMed: 33710525
DOI: 10.1007/s10974-021-09601-1 -
Journal of Clinical Medicine Feb 2021Myofibrillar myopathies (MFM) are heterogeneous hereditary muscle diseases with characteristic myopathological features of Z-disk dissolution and aggregates of its...
Myofibrillar myopathies (MFM) are heterogeneous hereditary muscle diseases with characteristic myopathological features of Z-disk dissolution and aggregates of its degradation products. The onset and progression of the disease are variable, with an elusive genetic background, and around half of the cases lacking molecular diagnosis. Here, we attempted to establish possible genetic foundations of MFM by performing whole exome sequencing (WES) in eleven unrelated families of 13 patients clinically diagnosed as MFM spectrum. A filtering strategy aimed at identification of variants related to the disease was used and included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of muscle-expressed genes, and analysis of the disease-associated interactome. Genetic diagnosis was possible in eight out of eleven cases. Putative causative mutations were found in the (two cases), , , and (four cases) genes, the latter typically presenting with a rigid spine syndrome. Moreover, a variety of additional, possibly phenotype-affecting variants were found. These findings indicate a markedly heterogeneous genetic background of MFM and show the usefulness of next generation sequencing in the identification of disease-associated mutations. Finally, we discuss the emerging concept of variant load as the basis of phenotypic heterogeneity.
PubMed: 33652732
DOI: 10.3390/jcm10050914