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Genes Nov 2019Duchenne muscular dystrophy (DMD) is a progressive hereditary muscular disease with X-linked recessive inheritance, that leads patients to premature death. The loss of... (Meta-Analysis)
Meta-Analysis
Duchenne muscular dystrophy (DMD) is a progressive hereditary muscular disease with X-linked recessive inheritance, that leads patients to premature death. The loss of dystrophin determines membrane instability, causing cell damage and inflammatory response. Macrophage migration inhibitory factor (MIF) is a cytokine that exerts pleiotropic properties and is implicated in the pathogenesis of a variety of diseases. Recently, converging data from independent studies have pointed to a possible role of MIF in dystrophic muscle disorders, including DMD. In the present study, we have investigated the modulation of MIF and MIF-related genes in degenerative muscle disorders, by making use of publicly available whole-genome expression datasets. We show here a significant enrichment of MIF and related genes in muscle samples from DMD patients, as well as from patients suffering from Becker's disease and limb-girdle muscular dystrophy type 2B. On the other hand, transcriptomic analysis of in vitro differentiated myotubes from healthy controls and DMD patients revealed no significant alteration in the expression levels of MIF-related genes. Finally, by analyzing DMD samples as a time series, we show that the modulation of the genes belonging to the MIF network is an early event in the DMD muscle and does not change with the increasing age of the patients, Overall, our analysis suggests that MIF may play a role in vivo during muscle degeneration, likely promoting inflammation and local microenvironment reaction.
Topics: Case-Control Studies; Datasets as Topic; Gene Expression Profiling; Gene Regulatory Networks; Healthy Volunteers; Humans; Intramolecular Oxidoreductases; Macrophage Migration-Inhibitory Factors; Muscle Fibers, Skeletal; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Duchenne; Myotonia Congenita; Signal Transduction
PubMed: 31752120
DOI: 10.3390/genes10110939 -
ELife Mar 2022To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of...
To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the ryanodine receptor 1 () gene; recessive mutations are accompanied by reduction of RyR1 expression and content in skeletal muscles and are associated with fiber hypotrophy and muscle weakness. Importantly, muscles of patients with recessive mutations exhibit increased content of class II histone deacetylases and of DNA genomic methylation. We recently created a mouse model knocked-in for the p.Q1970fsX16+ p.A4329D RyR1 mutations, which are isogenic to those carried by a severely affected child suffering from a recessive form of RyR1-related multi-mini core disease. The phenotype of the RyR1 mutant mice recapitulates many aspects of the clinical picture of patients carrying recessive mutations. We treated the compound heterozygous mice with a combination of two drugs targeting DNA methylases and class II histone deacetylases. Here, we show that treatment of the mutant mice with drugs targeting epigenetic enzymes improves muscle strength, RyR1 protein content, and muscle ultrastructure. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive mutations.
Topics: Animals; DNA; Disease Models, Animal; Histone Deacetylases; Humans; Methyltransferases; Mice; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Myotonia Congenita; Quality of Life; Ryanodine Receptor Calcium Release Channel
PubMed: 35238775
DOI: 10.7554/eLife.73718 -
Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium.The Journal of Clinical Investigation May 2021Troponin C (TnC) is a critical regulator of skeletal muscle contraction; it binds Ca2+ to activate muscle contraction. Surprisingly, the gene encoding fast skeletal TnC...
Troponin C (TnC) is a critical regulator of skeletal muscle contraction; it binds Ca2+ to activate muscle contraction. Surprisingly, the gene encoding fast skeletal TnC (TNNC2) has not yet been implicated in muscle disease. Here, we report 2 families with pathogenic variants in TNNC2. Patients present with a distinct, dominantly inherited congenital muscle disease. Molecular dynamics simulations suggested that the pathomechanisms by which the variants cause muscle disease include disruption of the binding sites for Ca2+ and for troponin I. In line with these findings, physiological studies in myofibers isolated from patients' biopsies revealed a markedly reduced force response of the sarcomeres to [Ca2+]. This pathomechanism was further confirmed in experiments in which contractile dysfunction was evoked by replacing TnC in myofibers from healthy control subjects with recombinant, mutant TnC. Conversely, the contractile dysfunction of myofibers from patients was repaired by replacing endogenous, mutant TnC with recombinant, wild-type TnC. Finally, we tested the therapeutic potential of the fast skeletal muscle troponin activator tirasemtiv in patients' myofibers and showed that the contractile dysfunction was repaired. Thus, our data reveal that pathogenic variants in TNNC2 cause congenital muscle disease, and they provide therapeutic angles to repair muscle contractility.
Topics: Binding Sites; Calcium; Humans; Molecular Dynamics Simulation; Muscle Contraction; Myotonia Congenita; Sarcomeres; Troponin C
PubMed: 33755597
DOI: 10.1172/JCI145700 -
Acta Neuropathologica Communications Aug 2020Ovine congenital progressive muscular dystrophy (OCPMD) was first described in Merino sheep flocks in Queensland and Western Australia in the 1960s and 1970s. The most...
Ovine congenital progressive muscular dystrophy (OCPMD) was first described in Merino sheep flocks in Queensland and Western Australia in the 1960s and 1970s. The most prominent feature of the disease is a distinctive gait with stiffness of the hind limbs that can be seen as early as 3 weeks after birth. The disease is progressive. Histopathological examination had revealed dystrophic changes specifically in type I (slow) myofibres, while electron microscopy had demonstrated abundant nemaline bodies. Therefore, it was never certain whether the disease was a dystrophy or a congenital myopathy with dystrophic features. In this study, we performed whole genome sequencing of OCPMD sheep and identified a single base deletion at the splice donor site (+ 1) of intron 13 in the type I myofibre-specific TNNT1 gene (KT218690 c.614 + 1delG). All affected sheep were homozygous for this variant. Examination of TNNT1 splicing by RT-PCR showed intron retention and premature termination, which disrupts the highly conserved 14 amino acid C-terminus. The variant did not reduce TNNT1 protein levels or affect its localization but impaired its ability to modulate muscle contraction in response to Ca levels. Identification of the causative variant in TNNT1 finally clarifies that the OCPMD sheep is in fact a large animal model of TNNT1 congenital myopathy. This model could now be used for testing molecular or gene therapies.
Topics: Animals; Disease Models, Animal; Muscle, Skeletal; Myotonia Congenita; Sheep; Sheep Diseases; Troponin T
PubMed: 32819427
DOI: 10.1186/s40478-020-01017-1 -
International Journal of Molecular... Oct 2020We have used the technique of polarized microfluorimetry to obtain new insight into the pathogenesis of skeletal muscle disease caused by the GlnPro substitution in...
We have used the technique of polarized microfluorimetry to obtain new insight into the pathogenesis of skeletal muscle disease caused by the GlnPro substitution in β-tropomyosin (Tpm2.2). The spatial rearrangements of actin, myosin and tropomyosin in the single muscle fiber containing reconstituted thin filaments were studied during simulation of several stages of ATP hydrolysis cycle. The angular orientation of the fluorescence probes bound to tropomyosin was found to be changed by the substitution and was characteristic for a shift of tropomyosin strands closer to the inner actin domains. It was observed both in the absence and in the presence of troponin, Ca and myosin heads at all simulated stages of the ATPase cycle. The mutant showed higher flexibility. Moreover, the GlnPro substitution disrupted the myosin-induced displacement of tropomyosin over actin. The irregular positioning of the mutant tropomyosin caused premature activation of actin monomers and a tendency to increase the number of myosin cross-bridges in a state of strong binding with actin at low Ca.
Topics: Actins; Adenosine Triphosphate; Amino Acid Substitution; Animals; Calcium; Cells, Cultured; Humans; Molecular Dynamics Simulation; Muscle Contraction; Myosins; Myotonia Congenita; Protein Domains; Rabbits; Tropomyosin; Troponin
PubMed: 33066566
DOI: 10.3390/ijms21207590 -
Genes Nov 2021Congenital myopathies are rare neuromuscular hereditary disorders that manifest at birth or during infancy and usually appear with muscle weakness and hypotonia. One of...
Congenital myopathies are rare neuromuscular hereditary disorders that manifest at birth or during infancy and usually appear with muscle weakness and hypotonia. One of such disorders, early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD, OMIM: 614399, MIM: 612453), is a rare autosomal recessive disorder caused by biallelic mutations (at homozygous or compound heterozygous status) in (multiple epidermal growth factor-like domains protein family). Here, we report two unrelated patients, who were born to consanguineous parents, having two novel deleterious variants. Interestingly, the presence of associated EMARDD has not been reported in Saudi Arabia, a highly consanguineous population. Moreover, both variants lead to a different phenotypic onset of mild and severe types. Our work expands phenotypic features of the disease and provides an opportunity for genetic counseling to the inflicted families.
Topics: Child, Preschool; Consanguinity; Humans; Infant; Male; Membrane Proteins; Myotonia Congenita; Pedigree; Phenotype
PubMed: 34828389
DOI: 10.3390/genes12111783 -
Acta Neuropathologica Aug 2020
Topics: DNA Repeat Expansion; Female; Genetic Predisposition to Disease; Humans; Male; Myotonia Congenita; Pedigree; Perilipin-4
PubMed: 32451610
DOI: 10.1007/s00401-020-02164-4 -
Bioorganic & Medicinal Chemistry Letters Aug 2019This letter describes progress towards an M PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant...
This letter describes progress towards an M PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.
Topics: Aldehyde Oxidase; Animals; Drug Discovery; Humans; Myotonia Congenita; Rats; Receptor, Muscarinic M4; Structure-Activity Relationship
PubMed: 31248774
DOI: 10.1016/j.bmcl.2019.06.032 -
Molecular Genetics & Genomic Medicine Aug 2019Early-onset myopathies show a wide spectrum of phenotypes and are composed of various types of inherited neuromuscular diseases, making it difficult to diagnose. TTN...
BACKGROUND
Early-onset myopathies show a wide spectrum of phenotypes and are composed of various types of inherited neuromuscular diseases, making it difficult to diagnose. TTN mutation-related myopathy is a known cause of early-onset myopathy. Since a next-generation sequencing (NGS) has enabled sequencing of the vast amount of DNA, TTN, which is the longest coding sequence of any human gene, mutations can now be revealed. We report a 10-year-old female with severe congenital muscular weakness and delayed motor development since birth.
METHODS
Next-generation sequencing as well as electromyography and muscle biopsy were performed.
RESULTS
To date, she is incapable of walking alone. Her younger sister had similar but more severe symptoms with respiratory failure. In electromyography, short-duration, small-amplitude motor unit action potential, and early recruitment patterns were observed in the involved proximal muscles, suggesting myopathy. Muscle histopathology showed a specific atrophy of increased fiber size variability, frequent nuclear internalization, as well as degeneration and regeneration of fibers with type I fiber predominance, consistent with the findings of a previous report about congenital titinopathy. A NGS study revealed two different possible pathogenic variants in TTN: (a) canonical splicing mutation in the intron 105 (c. 29963-1G>C) and (b) frameshift and truncating mutation in the exon 339 (c.92812dup/p.Arg30938LysfsTer15). All variants were confirmed by conventional Sanger sequencing.
CONCLUSION
We propose that unbiased genomic sequencing can be helpful in screening patients with early-onset myopathy.
Topics: Age of Onset; Child; Connectin; DNA Mutational Analysis; Exons; Female; High-Throughput Nucleotide Sequencing; Humans; Introns; Mutation; Myotonia Congenita; Pedigree
PubMed: 31332964
DOI: 10.1002/mgg3.866 -
Movement Disorders Clinical Practice Jan 2020
PubMed: 31970219
DOI: 10.1002/mdc3.12860