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Acta Myologica : Myopathies and... Mar 2019Tripartite motif-containing protein 32 () is a member of the TRIM ubiquitin E3 ligases which ubiquitinates different substrates in muscle including sarcomeric proteins....
Tripartite motif-containing protein 32 () is a member of the TRIM ubiquitin E3 ligases which ubiquitinates different substrates in muscle including sarcomeric proteins. Mutations in are associated with Limb-Girdle Muscular Dystrophy 2H. In a 66 old woman with disto-proximal myopathy, we identified a novel homozygous mutation of gene c.1781G > A (p. Ser594Asn) localised in the c-terminus NHL domain. Mutations of this domain have been also associated to Sarcotubular Myopathy (STM), a form of distal myopathy with peculiar features in muscle biopsy, now considered in the spectrum of LGMD2H. Muscle biopsy revealed severe abnormalities of the myofibrillar network with core like areas, lobulated fibres, whorled fibres and multiple vacuoles. Desmin and Myotilin stainings also pointed to accumulation as in Myofibrillar Myopathy. This report further confirms that STM and LGMD2H represent the same disorder and suggests to consider mutations in the genetic diagnosis of Sarcotubular Myopathy and Myofibrillar Myopathy.
Topics: Aged; Female; Humans; Muscular Dystrophies, Limb-Girdle; Mutation; Transcription Factors; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 31309175
DOI: No ID Found -
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 -
European Journal of Human Genetics :... Aug 2019We establish autosomal recessive DES variants p.(Leu190Pro) and a deep intronic splice variant causing inclusion of a frameshift-inducing artificial exon/intronic...
We establish autosomal recessive DES variants p.(Leu190Pro) and a deep intronic splice variant causing inclusion of a frameshift-inducing artificial exon/intronic fragment, as the likely cause of myopathy with cardiac involvement in female siblings. Both sisters presented in their twenties with slowly progressive limb girdle weakness, severe systolic dysfunction, and progressive, severe respiratory weakness. Desmin is an intermediate filament protein typically associated with autosomal dominant myofibrillar myopathy with cardiac involvement. However a few rare cases of autosomal recessive desminopathy are reported. In this family, a paternal missense p.(Leu190Pro) variant was viewed unlikely to be causative of autosomal dominant desminopathy, as the father and brothers carrying this variant were clinically unaffected. Clinical fit with a DES-related myopathy encouraged closer scrutiny of all DES variants, identifying a maternal deep intronic variant within intron-7, predicted to create a cryptic splice site, which segregated with disease. RNA sequencing and studies of muscle cDNA confirmed the deep intronic variant caused aberrant splicing of an artificial exon/intronic fragment into maternal DES mRNA transcripts, encoding a premature termination codon, and potently activating nonsense-mediate decay (92% paternal DES transcripts, 8% maternal). Western blot showed 60-75% reduction in desmin levels, likely comprised only of missense p.(Leu190Pro) desmin. Biopsy showed fibre size variation with increased central nuclei. Electron microscopy showed extensive myofibrillar disarray, duplication of the basal lamina, but no inclusions or aggregates. This study expands the phenotypic spectrum of recessive DES cardio/myopathy, and emphasizes the continuing importance of muscle biopsy for functional genomics pursuit of 'tricky' variants in neuromuscular conditions.
Topics: Adult; Base Sequence; Cardiomyopathies; Desmin; Exons; Family Health; Female; Genes, Recessive; Genetic Predisposition to Disease; Humans; Introns; Male; Muscular Dystrophies; Mutation, Missense; Myopathies, Structural, Congenital; Pedigree; RNA Splicing; Siblings
PubMed: 31024060
DOI: 10.1038/s41431-019-0393-6 -
Chinese Medical Journal Jan 2019Desminopathy, a hereditary myofibrillar myopathy, mainly results from the desmin gene (DES) mutations. Desminopathy involves various phenotypes, mainly including...
BACKGROUND
Desminopathy, a hereditary myofibrillar myopathy, mainly results from the desmin gene (DES) mutations. Desminopathy involves various phenotypes, mainly including different cardiomyopathies, skeletal myopathy, and arrhythmia. Combined with genotype, it helps us precisely diagnose and treat for desminopathy.
METHODS
Sanger sequencing was used to characterize DES variation, and then a minigene assay was used to verify the effect of splice-site mutation on pre-mRNA splicing. Phenotypes were analyzed based on clinical characteristics associated with desminopathy.
RESULTS
A splicing mutation (c.735+1G>T) in DES was detected in the proband. A minigene assay revealed skipping of the whole exon 3 and transcription of abnormal pre-mRNA lacking 32 codons. Another affected family member who carried the identical mutation, was identified with a novel phenotype of desminopathy, non-compaction of ventricular myocardium. There were 2 different phenotypes varied in cardiomyopathy and skeletal myopathy among the 2 patients, but no significant correlation between genotype and phenotype was identified.
CONCLUSIONS
We reported a novel phenotype with a splicing mutation in DES, enlarging the spectrum of phenotype in desminopathy. Molecular studies of desminopathy should promote our understanding of its pathogenesis and provide a precise molecular diagnosis of this disorder, facilitating clinical prevention and treatment at an early stage.
Topics: Animals; Asian People; Cardiomyopathies; Desmin; Electrocardiography; Female; Genotype; Humans; Male; Middle Aged; Muscular Dystrophies; Mutation; Pedigree; Phenotype
PubMed: 30614851
DOI: 10.1097/CM9.0000000000000001 -
Genes & Diseases Dec 2018Myofibrillar myopathies (MFMs) are rare genetic and slowly progressive neuromuscular disorders. Several pathogenic mutations have been reported in MFM-related genes...
Myofibrillar myopathies (MFMs) are rare genetic and slowly progressive neuromuscular disorders. Several pathogenic mutations have been reported in MFM-related genes including , , , or , , , and . Although MFMs is commonly inherited in an autosomal dominant manner, the inheritance pattern and novel mutated genes are not thoroughly elucidated in some cases. Here, we report discovery of a novel nonsense mutation in a 29-year-old Iranian male patient with motor disorders and deformity in his lower limbs. His parents are second cousins. Hereditary Motor Sensory Neuropathy as initial genetic diagnosis was ruled out. Whole exome sequencing using NGS on Illumina HiSeq4000 platform was performed to identify the disease and possible mutated gene(s). Our data analysis identified a homozygous nonsense unreported c.C415T (p.R139X) variant on kyphoscoliosis peptidase () gene (NM_178554: exon4). Sanger sequencing of this mutation has been performed for his other related family members. Sequencing and segregation analysis was confirmed the NGS results and autosomal recessive inheritance pattern of the disease.
PubMed: 30591934
DOI: 10.1016/j.gendis.2018.09.004 -
Journal of Neurology Feb 2019To describe adult-onset limb-girdle-type muscular dystrophy caused by biallelic variants in the PYROXD1 gene, which has been recently linked to early-onset congenital...
OBJECTIVE
To describe adult-onset limb-girdle-type muscular dystrophy caused by biallelic variants in the PYROXD1 gene, which has been recently linked to early-onset congenital myofibrillar myopathy.
METHODS
Whole exome sequencing was performed for adult-onset neuromuscular disease patients with no molecular diagnosis. Patients with PYROXD1 variants underwent clinical characterization, lower limb muscle MRI, muscle biopsy and spirometry. A yeast complementation assay was used to determine the biochemical consequences of the genetic variants.
RESULTS
We identified four patients with biallelic PYROXD1 variants. Three patients, who had symptom onset in their 20s or 30s, were homozygous for the previously described p.Asn155Ser. The fourth patient, with symptom onset at age 49, was compound heterozygous for p.Asn155Ser variant and previously unknown p.Tyr354Cys. All patients presented with a LGMD-type phenotype of symmetric muscle weakness and wasting. Symptoms started in proximal muscles of the lower limbs, and progressed slowly to involve also upper limbs in a proximal-predominant fashion. All patients remained ambulant past the age of 60. They had restrictive lung disease but no cardiac impairment. Muscle MRI showed strong involvement of anterolateral thigh muscles. Muscle biopsy displayed chronic myopathic changes. Yeast complementation assay demonstrated the p.Tyr354Cys mutation to impair PYROXD1 oxidoreductase ability.
CONCLUSION
PYROXD1 variants can cause an adult-onset slowly progressive LGMD-type phenotype.
Topics: Aged; Female; Finland; Genes, Recessive; Humans; Male; Muscular Dystrophies, Limb-Girdle; Oxidoreductases; Pedigree; Exome Sequencing
PubMed: 30515627
DOI: 10.1007/s00415-018-9137-8 -
Physiological Genomics Nov 2018Next-generation sequencing is commonly used to screen for pathogenic mutations in families with Mendelian disorders, but due to the pace of discoveries, gaps have...
Next-generation sequencing is commonly used to screen for pathogenic mutations in families with Mendelian disorders, but due to the pace of discoveries, gaps have widened for some diseases between genetic and pathophysiological knowledge. We recruited and analyzed 16 families with limb-girdle muscular dystrophy (LGMD) of Arab descent from Saudi Arabia and Sudan who did not have confirmed genetic diagnoses. The analysis included both traditional and next-generation sequencing approaches. Cellular and metabolic studies were performed on Pyroxd1 siRNA C2C12 myoblasts and controls. Pathogenic mutations were identified in eight of the 16 families. One Sudanese family of Arab descent residing in Saudi Arabia harbored a homozygous c.464A>G, p.Asn155Ser mutation in PYROXD1, a gene recently reported in association with myofibrillar myopathy and whose protein product reduces thiol residues. Pyroxd1 deficiency in murine C2C12 myoblasts yielded evidence for impairments of cellular proliferation, migration, and differentiation, while CG10721 (Pyroxd1 fly homolog) knockdown in Drosophila yielded a lethal phenotype. Further investigations indicated that Pyroxd1 does not localize to mitochondria, yet Pyroxd1 deficiency is associated with decreased cellular respiration. This study identified pathogenic mutations in half of the LGMD families from the cohort, including one in PYROXD1. Developmental impairments were demonstrated in vitro for Pyroxd1 deficiency and in vivo for CG10721 deficiency, with reduced metabolic activity in vitro for Pyroxd1 deficiency.
Topics: Adult; Animals; Animals, Genetically Modified; Cell Respiration; Cells, Cultured; Drosophila; Drosophila Proteins; Female; Humans; Male; Mice; Mitochondria, Muscle; Muscular Dystrophies, Limb-Girdle; Mutation; Myoblasts; Oxidoreductases Acting on Sulfur Group Donors; Pedigree; Saudi Arabia; Sudan
PubMed: 30345904
DOI: 10.1152/physiolgenomics.00036.2018 -
Physiological Genomics Dec 2018Equine myofibrillar myopathy (MFM) causes exertional muscle pain and is characterized by myofibrillar disarray and ectopic desmin aggregates of unknown origin. To...
Equine myofibrillar myopathy (MFM) causes exertional muscle pain and is characterized by myofibrillar disarray and ectopic desmin aggregates of unknown origin. To investigate the pathophysiology of MFM, we compared resting and 3 h postexercise transcriptomes of gluteal muscle and the resting skeletal muscle proteome of MFM and control Arabian horses with RNA sequencing and isobaric tags for relative and absolute quantitation analyses. Three hours after exercise, 191 genes were identified as differentially expressed (DE) in MFM vs. control muscle with >1 log fold change (FC) in genes involved in sulfur compound/cysteine metabolism such as cystathionine-beta-synthase ( CBS, ↓4.51), a cysteine and neutral amino acid membrane transporter ( SLC7A10, ↓1.80 MFM), and a cationic transporter (SLC24A1, ↓1.11 MFM). In MFM vs. control at rest, 284 genes were DE with >1 log FC in pathways for structure morphogenesis, fiber organization, tissue development, and cell differentiation including > 1 log FC in cardiac alpha actin ( ACTC1 ↑2.5 MFM), cytoskeletal desmoplakin ( DSP ↑2.4 MFM), and basement membrane usherin ( USH2A ↓2.9 MFM). Proteome analysis revealed significantly lower antioxidant peroxiredoxin 6 content (PRDX6, ↓4.14 log FC MFM), higher fatty acid transport enzyme carnitine palmitoyl transferase (CPT1B, ↑3.49 MFM), and lower sarcomere protein tropomyosin (TPM2, ↓3.24 MFM) in MFM vs. control muscle at rest. We propose that in MFM horses, altered cysteine metabolism and a deficiency of cysteine-containing antioxidants combined with a high capacity to oxidize fatty acids and generate ROS during aerobic exercise causes chronic oxidation and aggregation of key proteins such as desmin.
Topics: Animals; Antioxidants; Basement Membrane; Cell Differentiation; Cysteine; Fatty Acids; Female; Gene Expression Profiling; Horses; Male; Metabolic Networks and Pathways; Muscle Proteins; Muscle, Skeletal; Myopathies, Structural, Congenital; Peroxiredoxin VI; Physical Conditioning, Animal; Proteome; Reactive Oxygen Species
PubMed: 30289745
DOI: 10.1152/physiolgenomics.00044.2018 -
Molecular Genetics and Metabolism... Jun 2018
PubMed: 30023292
DOI: 10.1016/j.ymgmr.2018.02.002 -
BMC Neurology Jun 2018Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by...
BACKGROUND
Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by mutations of the filamin C gene (FLNC) located in the chromosome 7q32-q35 region. Genetic variations in the FLNC gene result in various clinical phenotypes.
CASE PRESENTATION
We describe a 43-year-old woman who suffered filamin C-related MFM, with symptoms first presenting in the proximal muscles of the lower limbs and eventually spreading to the upper limbs and distal muscles. The patient's serum level of creatine kinase was mildly increased. Mildy myopathic changes in the electromyographic exam and moderate lipomatous alterations in lower limb MRI were found. Histopathological examination revealed increased muscle fiber size variability, disturbances in oxidative enzyme activity, and the presence of abnormal protein aggregates and vacuoles in some muscle fibers. Ultrastructural analysis showed inclusions composed of thin filaments and interspersed granular densities. DNA sequencing analysis detected a novel 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the FLNC gene. The patient's father, sister, brother, three paternal aunts, one paternal uncle, and the uncle's son also had slowly progressive muscle weakness, and thus, we detected an autosomal dominant inheritance pattern of the disorder.
CONCLUSIONS
A novel heterogeneous 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the Ig-like domain 7 of the FLNC gene was found to cause filamin C-related MFM. This deletion in the FLNC gene causes protein aggregation, abnormalities in muscle structure, and impairment in muscle fiber function, which leads to muscle weakness.
Topics: Adult; Asian People; Exons; Female; Filamins; Heterozygote; Humans; Male; Mutation; Myopathies, Structural, Congenital; Pedigree; Phenotype; Sequence Deletion
PubMed: 29866061
DOI: 10.1186/s12883-018-1078-4