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Cells Dec 2022Desmin is the major intermediate filament protein of all three muscle cell types, and connects different cell organelles and multi-protein complexes such as the cardiac...
Desmin is the major intermediate filament protein of all three muscle cell types, and connects different cell organelles and multi-protein complexes such as the cardiac desmosomes. Several pathogenic mutations in the gene cause different skeletal and cardiac myopathies. However, the significance of the majority of missense variants is currently unknown, since functional data are lacking. To determine whether desmin missense mutations within the highly conserved 1A coil domain cause a filament assembly defect, we generated a set of variants with unknown significance and systematically analyzed the filament assembly using confocal microscopy in transfected SW-13, H9c2 cells and cardiomyocytes derived from induced pluripotent stem cells. We found that mutations in the N-terminal part of the 1A coil domain affect filament assembly, leading to cytoplasmic desmin aggregation. In contrast, mutant desmin in the C-terminal part of the 1A coil domain forms filamentous structures comparable to wild-type desmin. Our findings suggest that the N-terminal part of the 1A coil domain is a hot spot for pathogenic desmin mutations, which affect desmin filament assembly. This study may have relevance for the genetic counselling of patients carrying variants in the 1A coil domain of the gene.
Topics: Humans; Base Sequence; Cytoskeleton; Desmin; Intermediate Filaments; Muscular Diseases; Animals; Mice; Cell Line
PubMed: 36497166
DOI: 10.3390/cells11233906 -
Acta Myologica : Myopathies and... Dec 2021Myofibrillar myopathies are a heterogeneous group of neuromuscular disorders characterized by degeneration of Z-disk, causing the disintegration of myofibrils. They may...
Myofibrillar myopathies are a heterogeneous group of neuromuscular disorders characterized by degeneration of Z-disk, causing the disintegration of myofibrils. They may be caused by mutations in different genes, among these, the BAG3 gene (Bcl-2 associed-athanogene-3) encodes a multidomain protein that plays an important role in many cellular processes. We report the case of a 16-year-old male who at 4 years of age presented with a hypertrophic obstructive cardiomyopathy, then developed axonal sensory motor polyneuropathy, muscle weakness, rigid spine, severe kyphoscoliosis and respiratory failure. Muscle biopsy showed the typical hallmark of myofibrillar myopathy with abnormal cytoplasmic expression of multiple proteins. Ade novo heterozygous common mutation in the BAG3 gene with a c.626C > T (p.Pro209Leu) was discovered on NGS genetic analysis. Mutations in the BAG3 gene are causes of a severe and progressive condition and natural history data are important to be collected. An early diagnosis is critical for prognostic implications in cardiomyopathy and respiratory failure treatment.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Apoptosis Regulatory Proteins; Cardiomyopathies; Child; Humans; Male; Mutation; Myopathies, Structural, Congenital
PubMed: 35047758
DOI: 10.36185/2532-1900-061 -
Frontiers in Neurology 2019Myofibrillar myopathies (MFM) are a clinically and genetically heterogenous group of inherited myopathies characterized by aggregation of Z-disc proteins. Mutations in...
Myofibrillar myopathies (MFM) are a clinically and genetically heterogenous group of inherited myopathies characterized by aggregation of Z-disc proteins. Mutations in desmin account for ~7% of MFM. We report here a Hmong family with an autosomal dominant MFM caused by a novel variant in the desmin gene. The proband presented with lower limb followed by upper limb weakness starting in the 5th decade. On examination, there was distal more than proximal muscle weakness. One sibling was similarly affected, while another had an asymptomatic elevation of creatine kinase. Genetic testing revealed a novel p.Ser13Tyr variant, which was predicted by algorithms to alter protein function. Muscle biopsy revealed a MFM. Muscle MRI demonstrated selective involvement of the tensor fasciae latae, semitendinosus, sartorius, gracilis, gastrocnemius, soleus, and peroneus longus muscles. In this family, the histological and MRI findings assisted in the interpretation of genetic testing results.
PubMed: 31998224
DOI: 10.3389/fneur.2019.01375 -
International Journal of Molecular... Dec 2023Small heat shock proteins (sHsps) are a family of ATP-independent molecular chaperones that function as "holdases" and prevent protein aggregation due to changes in...
Small heat shock proteins (sHsps) are a family of ATP-independent molecular chaperones that function as "holdases" and prevent protein aggregation due to changes in temperature, pH, or oxidation state. sHsps have a conserved α-crystallin domain (ACD), which forms the dimer building block, flanked by variable N- and C-terminal regions. sHsps populate various oligomeric states as a function of their sequestrase activity, and these dynamic structural features allow the proteins to interact with a plethora of cellular substrates. However, the molecular mechanisms of their dynamic conformational assembly and the interactions with various substrates remains unclear. Therefore, it is important to gain insight into the underlying physicochemical properties that influence sHsp structure in an effort to understand their mechanism(s) of action. We evaluated several disease-relevant mutations, D109A, F113Y, R116C, R120G, and R120C, in the ACD of HspB5 for changes to in vitro chaperone activity relative to that of wildtype. Structural characteristics were also evaluated by ANS fluorescence and CD spectroscopy. Our results indicated that mutation Y113F is an efficient holdase, while D109A and R120G, which are found in patients with myofibrillar myopathy and cataracts, respectively, exhibit a large reduction in holdase activity in a chaperone-like light-scattering assay, which indicated alterations in substrate-sHsp interactions. The extent of the reductions in chaperone activities are different among the mutants and specific to the substrate protein, suggesting that while sHsps are able to interact with many substrates, specific interactions provide selectivity for some substrates compared to others. This work is consistent with a model for chaperone activity where key electrostatic interactions in the sHsp dimer provide structural stability and influence both higher-order sHsp interactions and facilitate interactions with substrate proteins that define chaperone holdase activity.
Topics: Humans; alpha-Crystallins; Biological Assay; Heat-Shock Proteins, Small; Molecular Chaperones; Protein Folding
PubMed: 38203641
DOI: 10.3390/ijms25010471 -
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 -
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