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Journal of Neuropathology and... Aug 2022Desmin (DES) is the main intermediate muscle filament that connects myofibrils individually and with the nucleus, sarcolemma, and organelles. Pathogenic variants of DES...
Desmin (DES) is the main intermediate muscle filament that connects myofibrils individually and with the nucleus, sarcolemma, and organelles. Pathogenic variants of DES cause desminopathy, a disorder affecting the heart and skeletal muscles. We aimed to analyze the clinical features, morphology, and distribution of desmin aggregates in skeletal muscle biopsies of patients with desminopathy and to correlate these findings with the type and location of disease-causing DES variants. This retrospective study included 30 patients from 20 families with molecularly confirmed desminopathy from 2 neuromuscular referral centers. We identified 2 distinct patterns of desmin aggregates: well-demarcated subsarcolemmal aggregates and diffuse aggregates with poorly delimited borders. Pathogenic variants located in the 1B segment and the tail domain of the desmin molecule are more likely to present with early-onset cardiomyopathy compared to patients with variants in other segments. All patients with mutations in the 1B segment had well-demarcated subsarcolemmal aggregates, but none of the patients with variants in other desmin segments showed such histological features. We suggest that variants located in the 1B segment lead to well-shaped subsarcolemmal desmin aggregation and cause disease with more frequent cardiac manifestations. These findings will facilitate early identification of patients with potentially severe cardiac syndromes.
Topics: Cardiomyopathies; Desmin; Humans; Muscle, Skeletal; Mutation; Phenotype; Retrospective Studies
PubMed: 35898174
DOI: 10.1093/jnen/nlac063 -
Experimental Cell Research Oct 2019Desminopathies are a type of myofibrillar myopathy resulting from mutations in DES, encoding the intermediate filament protein desmin. They display heterogeneous...
Desminopathies are a type of myofibrillar myopathy resulting from mutations in DES, encoding the intermediate filament protein desmin. They display heterogeneous phenotypes, suggesting environment influences. Patient muscle proteins show oxidative features linking oxidative stress, protein aggregation, and abnormal protein deposition. To improve understanding of redox balance in desminopathies, we further developed cellular models of four pathological mutants localized in 2B helical domain (the most important region for desmin polymerization) to explore desmin behavior upon oxidative stress. We show that the mutations desQ389P and desD399Y share common stress-induced aggregates, desR406W presents more scattered cytoplasmic aggregative pattern, and pretreatment with N-acetyl-l-cysteine (NAC), an antioxidant molecule, prevents all type of aggregation. Mutants desD399Y and desR406W had delayed oxidation kinetics following HO stress prevented by NAC pretreatment. Further, we used AAV-injected mouse models to confirm in vivo effects of N-acetyl-l-cysteine. AAV-desD399Y-injected muscles displayed similar physio-pathological characteristics as observed in patients. However, after 2 months of NAC treatment, they did not have reduced aggregates. Finally, in both models, stress induced some post-translational modifications changing Isoelectric Point, such as potential hyperphosphorylations, and/or molecular weight of human desmin by proteolysis. However, each mutant presented its own pattern that seemed to be post-aggregative. In conclusion, our results indicate that individual desmin mutations have unique pathological molecular mechanisms partly linked to alteration of redox homeostasis. Integrating these mutant-specific behaviors will be important when considering future therapeutics.
Topics: Amino Acid Substitution; Animals; Antioxidants; Cardiomyopathies; Cells, Cultured; Desmin; Disease Models, Animal; Homeostasis; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle Proteins; Muscle, Skeletal; Muscular Dystrophies; Mutant Proteins; Oxidation-Reduction; Oxidative Stress; Protein Processing, Post-Translational
PubMed: 31369751
DOI: 10.1016/j.yexcr.2019.111539 -
Stem Cell Research Oct 2023Here we introduce the human induced pluripotent stem cell (hiPSC) line HIMRi001-A generated from cultured dermal fibroblasts of a 60-year-old male patient with a...
Here we introduce the human induced pluripotent stem cell (hiPSC) line HIMRi001-A generated from cultured dermal fibroblasts of a 60-year-old male patient with a myofibrillar myopathy, carrying a heterozygous c.4984C > T [p.Q1662X] mutation in the filamin C (FLNC)-gene, via lentiviral expression of OCT4, SOX2, KLF4 and c-MYC. HIMRi001-A displays typical embryonic stem cell-like morphology, carries the c.4984C > T FLNC gene mutation, expressed several pluripotent stem cell makers, retained normal karyotype (46, XY) and holds the potential to differentiate in all three germ layers. We postulate that HIMRi001-A can be used for the elucidation of FLNC-associated pathomechanisms and for developing new therapeutic options.
Topics: Male; Humans; Middle Aged; Induced Pluripotent Stem Cells; Kruppel-Like Factor 4; Pluripotent Stem Cells; Fibroblasts; Mutation; Cell Differentiation
PubMed: 37748332
DOI: 10.1016/j.scr.2023.103210 -
Journal of the Neurological Sciences Sep 2020
Topics: Humans; Muscle, Skeletal; Muscular Diseases
PubMed: 32619840
DOI: 10.1016/j.jns.2020.116999 -
Molecular Genetics & Genomic Medicine Aug 2019Due to inconsistencies with reported myofibrillar myopathy (MFM), including autosomal dominant inheritance, late onset and a slowly progressive course, the severe,...
BACKGROUND
Due to inconsistencies with reported myofibrillar myopathy (MFM), including autosomal dominant inheritance, late onset and a slowly progressive course, the severe, recessively inherited form of CRYAB (alpha-B crystallin) gene-related infantile MFM has been suggested. Here, we report an infant in a Chinese family with fatal neonatal-onset hypertonic MFM with a novel CRYAB homozygous variant (c.3G > A (p.Met1?)).
METHODS
Muscle biopsy indicated that muscle fibers showed a uniformly small diameter, cell atrophy, and visible focal muscle fiber degeneration and necrosis consistent with myogenic myopathy. We performed the whole exome sequencing of pathogenic genes and identified it as MFM.
RESULTS
The proband presented with profound muscle stiffness, progressive respiratory distress and a concurrent abnormal increase in myocardial enzymogram, and the patient died in the 17th month of life. Muscle biopsy and electron microscopy results were consistent with ultramicroscopic myogenic damage and pathological changes. Mutation analysis of the proband identified a novel rare homozygous mutation in the initiation codon of the CRYAB gene, which was inherited from currently asymptomatic, heterozygous carrier parents, and his heterozygous biological brother is unaffected.
CONCLUSIONS
This article reports one infant with CRYAB-related neonatal onset MFM with a novel homozygous variant in CRYAB. To our knowledge, this is the first reported case of infantile alpha-Bcrystallinopathy in the Chinese population.
Topics: Asian People; Biopsy; Cardiomyopathies; Cataract; Codon, Initiator; DNA Mutational Analysis; Fatal Outcome; Homozygote; Humans; Infant; Male; Muscles; Muscular Diseases; Mutation; Exome Sequencing; alpha-Crystallin B Chain
PubMed: 31215171
DOI: 10.1002/mgg3.825 -
BMJ Case Reports Dec 2023Myofibrillar myopathies (MFMs) are a group of rare genetic disorders that affect the function of skeletal, cardiac and smooth muscle.MFM exhibits a considerable degree...
Myofibrillar myopathies (MFMs) are a group of rare genetic disorders that affect the function of skeletal, cardiac and smooth muscle.MFM exhibits a considerable degree of clinical heterogeneity. In numerous instances of MFM, muscle weakness is the predominant manifestation. Certain MFM subtypes are distinguished by respiratory and cardiac impairment.There is little information available about anaesthetic management in MFM, and even less is known about obstetric anaesthesia.A successful case of a patient with MFM undergoing a caesarean section under combined neuraxial anaesthesia is reported. The patient experienced no complications, and functional recovery was swift.
Topics: Pregnancy; Humans; Female; Cesarean Section; Myopathies, Structural, Congenital; Muscle Weakness; Anesthetics; Muscle, Skeletal
PubMed: 38050391
DOI: 10.1136/bcr-2023-257198 -
Medicine Jan 2022Mutations in Bcl-2-associated athanogene-3 (BAG-3) can cause a rare subtype of myofibrillar myopathies (MFMs), characterized by progressive muscle weakness,...
RATIONALE
Mutations in Bcl-2-associated athanogene-3 (BAG-3) can cause a rare subtype of myofibrillar myopathies (MFMs), characterized by progressive muscle weakness, cardiomyopathy, and severe respiratory insufficiency in childhood. Little is known about diaphragmatic function in BAG-3 MFM. To our knowledge, this is the first case report of detailed evaluation of diaphragmatic function with ultrasound in BAG-3 MFM.
PATIENT CONCERN
We describe the case of a 15-year-old girl who complained of fever and shortness of breath. Diaphragmatic sonography revealed bilateral diaphragmatic paralysis. Shortness of breath progressed to respiratory failure approximately 3 months later.
DIAGNOSIS
A neurologist was consulted and genetic sequencing identified a p.Pro209Leu mutation in BAG-3, yielding diagnosis of BAG-3 MFM leading to bilateral diaphragmatic paralysis.
INTERVENTIONS
Respiratory muscle training and long-term mechanical ventilation.
OUTCOMES
It is quite unfortunate for this patient to have a poor prognosis due to the lack of effective treatment for this genetic disorder.
LESSONS
This case provides more clinical information for this rare disease which may cause severe diaphragm pathological damage leading to respiratory failure in BAG3 MFM and a future study with a systematic evaluation of a greater number of patients will be necessary to characterize this population.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Apoptosis Regulatory Proteins; Diaphragm; Dyspnea; Female; Humans; Muscle Weakness; Myopathies, Structural, Congenital; Respiratory Paralysis; Transcription Factors
PubMed: 35029900
DOI: 10.1097/MD.0000000000028484 -
Frontiers in Neurology 2020[This corrects the article DOI: 10.3389/fneur.2020.01014.].
[This corrects the article DOI: 10.3389/fneur.2020.01014.].
PubMed: 33488509
DOI: 10.3389/fneur.2020.636981 -
Molecular Therapy. Nucleic Acids Mar 2022FilaminC (Flnc) is a member of the actin binding protein family, which is preferentially expressed in the cardiac and skeletal muscle tissues. Although it is known to...
FilaminC (Flnc) is a member of the actin binding protein family, which is preferentially expressed in the cardiac and skeletal muscle tissues. Although it is known to interact with proteins associated with myofibrillar myopathy, its unique role in skeletal muscle remains largely unknown. In this study, we identify the biological functions of Flnc and using chicken primary myoblast cells and animal models, respectively. From the results, we observe that the growth rate and mass of the skeletal muscle of fast-growing chickens (broilers) were significantly higher than those in slow-growing chickens (layers). Furthermore, we find that the expression of Flnc in the skeletal muscle of broilers was higher than that in the layers. Our results indicated that Flnc was highly expressed in the skeletal muscle, especially in the skeletal muscle of broilers than in layers. This suggests that Flnc plays a positive regulatory role in myoblast development. Flnc knockdown resulted in muscle atrophy, whereas the overexpression of Flnc promotes muscle hypertrophy in an animal model. We also found that Flnc interacted with dishevelled-2 (Dvl2), activated the wnt/β-catenin signaling pathway, and controlled skeletal muscle development. Flnc also antagonized the LC3-mediated autophagy system by decreasing Dvl2 ubiquitination. Moreover, Flnc knockdown activated and significantly increased mitophagy. In summary, these results indicate that the absence of Flnc induces autophagy or mitophagy and regulates muscle atrophy.
PubMed: 34976434
DOI: 10.1016/j.omtn.2021.11.022 -
Frontiers in Neurology 2022The gene encodes desmin, a key intermediate filament of skeletal, cardiac and smooth muscle. Pathogenic variants produce a range of skeletal and cardiac muscle...
The gene encodes desmin, a key intermediate filament of skeletal, cardiac and smooth muscle. Pathogenic variants produce a range of skeletal and cardiac muscle disorders collectively known as the desminopathies. We report three desminopathy cases which highlight the phenotypic heterogeneity of this disorder and discuss various factors that may contribute to the clinical differences seen between patients with different desmin variants and also between family members with the same variant.
PubMed: 36726751
DOI: 10.3389/fneur.2022.1110934