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Neurological Sciences : Official... May 2022Hereditary myopathy with early respiratory failure (HMERF) is a subtype of myofibrillar myopathy. Mutations located on exon 344 of the titin-A band, the 119th...
Hereditary myopathy with early respiratory failure (HMERF) is a subtype of myofibrillar myopathy. Mutations located on exon 344 of the titin-A band, the 119th fibronectin-3 domain (FN 119), are responsible for HMERF. In this article, we retrospectively analyzed the clinical features, findings of muscle imaging, muscle pathology, immunohistochemistry, and ultrastructural characteristics of seven patients diagnosed with HMERF at a single center in China. Muscle MRI showed the involvement of semitendinosus in four patients. The common pathological features were variability in fiber diameter, increased internal nuclei, endomysial fibrosis, and cytoplasmic bodies. On immunohistochemical examination, the cytoplasmic bodies stained positive for calpain-3, p53, and programmed death-ligand 1. Electron microscopy showed cytoplasmic bodies, distorted sarcomere architecture, glycogen pool, and subsarcolemmal accumulation of mitochondria and lysosomes. We retrospectively reviewed four reported HMERF patients in China. Among the 11 patients, the median age at onset was 34 years (range 14-54). Allelic frequency of mutation c.95195C > T was 36.36%. This study characterizes the phenotype and genotype spectrum of HMERF in China.
Topics: Genetic Diseases, Inborn; Humans; Molecular Biology; Muscle, Skeletal; Muscular Diseases; Mutation; Respiratory Insufficiency; Retrospective Studies
PubMed: 34839411
DOI: 10.1007/s10072-021-05783-1 -
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 -
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 -
PloS One 2021αB-crystallin (heat shock protein β5/HSPB5) is a member of the family of small heat shock proteins that is expressed in various organs of the human body including eye...
αB-crystallin (heat shock protein β5/HSPB5) is a member of the family of small heat shock proteins that is expressed in various organs of the human body including eye lenses and muscles. Therefore, mutations in the gene of this protein (CRYAB) might have many pathological consequences. A new mutation has recently been discovered in the α-crystallin domain of this chaperone protein which replaces aspartate 109 with alanine (D109A). This mutation can cause myofibrillar myopathy (MFM), cataracts, and cardiomyopathy. In the current study, several spectroscopic and microscopic analyses, as well as gel electrophoresis assessment were applied to elucidate the pathogenic contribution of human αB-crystallin bearing D109A mutation in development of eye lens cataract and myopathies. The protein oligomerization, chaperone-like activity and chemical/thermal stabilities of the mutant and wild-type protein were also investigated in the comparative assessments. Our results suggested that the D109A mutation has a significant impact on the important features of human αB-crystallin, including its structure, size of the protein oligomers, tendency to form amyloid fibrils, stability, and chaperone-like activity. Given the importance of aspartate 109 in maintaining the proper structure of the α-crystallin domain, its role in the dimerization and chaperone-like activity, as well as preserving protein stability through the formation of salt bridges; mutation at this important site might have critical consequences and can explain the genesis of myopathy and cataract disorders. Also, the formation of large light-scattering aggregates and disruption of the chaperone-like activity by D109A mutation might be considered as important contributing factors in development of the eye lens opacity.
Topics: Cardiomyopathies; Cataract; Humans; Models, Molecular; Point Mutation; Protein Conformation; Protein Folding; Protein Multimerization; Protein Stability; alpha-Crystallin B Chain
PubMed: 34843556
DOI: 10.1371/journal.pone.0260306 -
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 -
Journal of Neurology Feb 2024To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy.
OBJECTIVE
To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy.
METHODS
This study enrolled eight affected individuals from a single family and included a comprehensive evaluation of the clinical phenotype, neurophysiologic testing, muscle MRI, muscle biopsy and western blot of BAG3 protein in skeletal muscle. Genetic workup included whole exome sequencing and segregation analysis of the detected variant in BAG3.
RESULTS
Seven patients developed slowly progressive and symmetric distal weakness and atrophy of lower limb muscles, along with absent Achilles reflexes. The mean age of onset was 46 years. The neurophysiological examination was consistent with the diagnosis of distal motor neuronopathy. One 57-year-old female patient was minimally symptomatic. The pattern of inheritance was autosomal dominant, with one caveat: one female patient who was an obligate carrier of the variant died at the age of 73 years without exhibiting any muscle weakness. The muscle biopsies revealed neurogenic changes. A novel heterozygous truncating variant c.1513_1514insGGAC (p.Val505GlyfsTer6) in the gene BAG3 was identified in all affected family members.
CONCLUSIONS
We report an autosomal dominant adult-onset distal hereditary motor neuronopathy with incomplete penetrance in women as a new phenotype related to a truncating variant in the BAG3 gene. Our findings expand the phenotypic spectrum of BAG3-related disorders, which previously included dilated cardiomyopathy, myofibrillar myopathy and adult-onset Charcot-Marie-Tooth type 2 neuropathy. Variants in BAG3 should be considered in the differential diagnosis of distal hereditary motor neuronopathies.
Topics: Adult; Humans; Female; Middle Aged; Aged; Pedigree; Charcot-Marie-Tooth Disease; Phenotype; Muscle, Skeletal; Muscular Atrophy, Spinal; Mutation; Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins
PubMed: 37907725
DOI: 10.1007/s00415-023-12039-9 -
Journal of Neuromuscular Diseases 2023We describe a cohort of five patients with limb-girdle muscular dystrophy (LGMD) 2G/LGMD-R7 in a South-east Asian cohort.
Unique Clinical, Radiological and Histopathological Characteristics of a Southeast Asian Cohort of Patients with Limb-Girdle Muscular Dystrophy 2G/LGMD-R7-Telethonin-Related.
AIM
We describe a cohort of five patients with limb-girdle muscular dystrophy (LGMD) 2G/LGMD-R7 in a South-east Asian cohort.
BACKGROUND
LGMD2G/LGMD-R7-telethonin-related is caused by mutations in the TCAP gene that encodes for telethonin.
METHODS
We identified consecutive patients with LGMD2G/LGMD-R7-telethonin-related, diagnosed at the National Neuroscience Institute (NNI) and National University Hospital (NUH) between January 2000 and June 2021.
RESULTS
At onset, three patients presented with proximal lower limb weakness, one patient presented with Achilles tendon contractures, and one patient presented with delayed gross motor milestones. At last follow up, three patients had a limb girdle pattern of muscle weakness and two had a facioscapular humeral pattern of weakness. Whole body muscle MRI performed for one patient with a facioscapular-humeral pattern of weakness showed a pattern of muscle atrophy similar to facioscapular-humeral dystrophy. One patient had histological features consistent with myofibrillar myopathy; electron microscopy confirmed the disruption of myofibrillar architecture. One patients also had reduced staining to telethonin antibody on immunohistochemistry.
CONCLUSION
We report the unique clinical and histological features of a Southeast Asian cohort of five patients with LGMD2G/LGMD-R7-telethonin-related muscular dystrophy and further expand its clinical and histopathological spectrum.
Topics: Humans; Connectin; Southeast Asian People; Muscular Dystrophies, Limb-Girdle; Muscle Weakness
PubMed: 36463458
DOI: 10.3233/JND-221517 -
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