Prospects for the Etiotropic Treatment of Dysferlinopathy

2021 ◽  
Vol 76 (3) ◽  
pp. 307-316
Author(s):  
Alisa V. Ivanova ◽  
Svetlana A. Smirnikhina ◽  
Alexander V. Lavrov
Keyword(s):  
Stop Codon ◽  
Experimental Studies ◽  
Neuromuscular Diseases ◽  
Exon Skipping ◽  
Autosomal Recessive Inheritance ◽  
Primary Lesion ◽  
Muscular Dystrophies ◽  
Human Skeletal Muscle Cells ◽  
Anterior Tibial ◽  
Trans Splicing

Dysferlinopathies belong to a phenotypically heterogeneous group of neuromuscular diseases caused by mutations in the DYSF gene, which disrupt the expression of dysferlin protein in human skeletal muscle cells. These pathologies are of an autosomal recessive inheritance pattern, their prevalence is 1: 200000. Dysferlinopathies include diseases such as Miyoshi myopathy with primary lesion of the distal fragments of the lower extremities and limb-gridle muscular dystrophy type 2B with primary lesion of the proximal fragments of both the lower and upper limbs, also distal myopathy with anterior tibial onset (DMAT). Nowdays, there are various pathogenetic and symptomatic treatments for hereditary muscular dystrophies but there are very few registered drugs for the etiological treatment of these diseases. This review discusses the main modern methods of gene therapy that can be used to treat dysferlinopathies, such as stop-codon passing, exon skipping, overexpression of other genes, gene transfer, splicosome-mediated trans-splicing, and also describes the latest experimental studies using these methods. In conclusion, exon-skipping and trans-splicing have been identified as the most optimal approaches in the treatment of muscular dystrophies, in particular dysferlinopathies.

scholarly journals Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies

2021 ◽  
Vol 22 (10) ◽  
pp. 5276
Author(s):  
Coralie Croissant ◽  
Romain Carmeille ◽  
Charlotte Brévart ◽  
Anthony Bouter
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Genetic Disorders ◽  
Muscle Cells ◽  
Cell Types ◽  
Clinical Severity ◽  
Skeletal Muscle Cells ◽  
Muscular Dystrophies ◽  
Membrane Repair ◽  
Human Skeletal Muscle Cells

Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca2+). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.

scholarly journals Identification of the genomic mutation in Epha4rb-2J/rb-2J mice

Genome ◽  
2016 ◽  
Vol 59 (7) ◽  
pp. 439-448 ◽  
Author(s):  
Siti W. Mohd-Zin ◽  
Nor-Linda Abdullah ◽  
Aminah Abdullah ◽  
Nicholas D.E. Greene ◽  
Pike-See Cheah ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Tyrosine Kinases ◽  
Stop Codon ◽  
Cell Signalling ◽  
Experimental Studies ◽  
Premature Stop Codon ◽  
Mouse Mutant ◽  
Functional Studies ◽  
Base Pair Deletion ◽  
Numerous Cell

The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4rb-2J/rb-2J, is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or “hopping gait” phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4rb-2J corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4rb-2J allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein–protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype.

Differential diagnosis of Duchenne muscular dystrophy

2021 ◽  
Vol 2 (3) ◽  
pp. 159-166
Author(s):  
Alexey L. Kurenkov ◽  
Lyudmila M. Kuzenkova ◽  
Lale A. Pak ◽  
Bella I. Bursagova ◽  
Tatyana V. Podkletnova ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Damage ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Neuromuscular Diseases ◽  
Muscular Dystrophies ◽  
Juvenile Form ◽  
Pathogenic Variants

Duchenne muscular dystrophy (DMD) is a disease with an X-linked recessive type of inheritance, belonging to a group of disorders with primary muscle damage, caused by pathogenic variants in the DMD gene and associated with dysfunction of the dystrophin protein. Since DMD is manifested by the gradual development of progressive, mainly proximal muscle weakness, the differential diagnosis is primarily carried out in the group of diseases with muscle damage - myopathies. Among these diseases, the leading candidates for differential diagnosis are hereditary myopathies (limb-girdle muscular dystrophies, facioscapulohumeral dystrophy, congenital muscular dystrophies, glycogenoses - the most common juvenile form of glycogenosis type II (Pompe disease)) and, much less often, congenital myopathies and other conditions of neuromuscular diseases). When conducting a differential diagnosis in a child with suspected DMD, the age of the onset of the disease, early initial clinical manifestations and the development of symptoms as they grow, genealogical analysis, laboratory tests (the level of creatine kinase, aspartate aminotransferase, alanine aminotransferase in blood serum), instrumental (electromyography, magnetic resonance imaging of the brain and muscles) and molecular genetics (polymerase chain reaction, multiplex ligation-dependent probe amplification, next-generation sequencing, Sanger sequencing, etc.) of studies, and in some cases, muscle biopsy data. Knowledge of the nuances of the differential diagnosis allows establishing a genetic diagnosis of DMD as early as possible, which is extremely important for the formation of the prognosis of the disease and the implementation of all available treatment methods, including pathogenetic therapy, and is also necessary for medical and genetic counselling of families with DMD patients.

scholarly journals Dystrophin rescue by trans -splicing: a strategy for DMD genotypes not eligible for exon skipping approaches

2013 ◽  
Vol 41 (17) ◽  
pp. 8391-8402 ◽  
Author(s):  
Stéphanie Lorain ◽  
Cécile Peccate ◽  
Maëva Le Hir ◽  
Graziella Griffith ◽  
Susanne Philippi ◽  
...  
Keyword(s):  
Exon Skipping ◽  
Trans Splicing

Secondary Bone Defect in Neuromuscular Diseases in Childhood: A Longitudinal “Muscle-Bone Unit” Analysis

2018 ◽  
Vol 49 (06) ◽  
pp. 397-400 ◽  
Author(s):  
C. Ribstein ◽  
D. Courteix ◽  
N. Rabiau ◽  
C. Bommelaer ◽  
Y. Bourdeau ◽  
...  
Keyword(s):  
Bone Defect ◽  
Functional Relationship ◽  
Bone Markers ◽  
Neuromuscular Diseases ◽  
Muscular Dystrophies ◽  
Mineral Density ◽  
Z Scores ◽  
Spinal Muscular Atrophies ◽  
Total Body

AbstractTo evaluate the potential bone defect in neuromuscular diseases, we conducted a longitudinal study including three groups of patients: 14 Duchenne muscular dystrophies (DMD) and 2 limb-girdle muscular dystrophies (LGMD); 3 Becker muscular dystrophies (BeMD) and 7 spinal muscular atrophies (SMA). Yearly osteodensitometries assessed body composition and bone mineral density (BMD) associated with bone markers and leptin. Along the 7-year study, 107 osteodensitometries showed that bone status evolved to osteopenia in most patients except BeMD. When analyzing the crude values, BMD improved with age in BeMD and SMA but not in DMD/LGMD. The correlation using the Z-scores displayed a decrease in BMD with age in DMD/LGMD for all regions, in SMA at total body less head, whereas BMD increased in BeMD at lumbar spine. As observed in healthy persons, muscular mass and bone tissue were significantly correlated. Glucocorticoids were deleterious on trabecular and cortical bone. Leptin was high in most patients and correlated to fat mass and bone parameters. This study confirms a secondary bone defect in neuromuscular diseases, further confirming the functional relationship between bone and muscle and arguing for regular bone follow-up in patients to prevent fracture risk. Adipose tissue seems to interfere with bone remodeling in neuromuscular diseases.

scholarly journals Molecular Diagnosis and Novel Therapies for Neuromuscular Diseases

2020 ◽  
Vol 10 (3) ◽  
pp. 129 ◽  
Author(s):  
Rika Maruyama ◽  
Toshifumi Yokota
Keyword(s):  
Muscular Dystrophy ◽  
Molecular Diagnosis ◽  
Musculoskeletal Diseases ◽  
Neuromuscular Diseases ◽  
Exon Skipping ◽  
Gene Replacement ◽  
Research Progress ◽  
Novel Therapies ◽  
Therapeutic Outcomes ◽  
Approved Drugs

With the development of novel targeted therapies, including exon skipping/inclusion and gene replacement therapy, the field of neuromuscular diseases has drastically changed in the last several years. Until 2016, there had been no FDA-approved drugs to treat Duchenne muscular dystrophy (DMD), the most common muscular dystrophy. However, several new personalized therapies, including antisense oligonucleotides eteplirsen for DMD exon 51 skipping and golodirsen and viltolarsen for DMD exon 53 skipping, have been approved in the last 4 years. We are witnessing the start of a therapeutic revolution in neuromuscular diseases. However, the studies also made clear that these therapies are still far from a cure. Personalized genetic medicine for neuromuscular diseases faces several key challenges, including the difficulty of obtaining appropriate cell and animal models and limited its applicability. This Special Issue “Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases” highlights key areas of research progress that improve our understanding and the therapeutic outcomes of neuromuscular diseases in the personalized medicine era.

Absence of Band 3 in Severe Dyserythropoietic/Hemolytic Anemia with Complete Distal Renal Acidosis and a Novel Homozygous Exon 12 C.1430C>a (p.Ser477X) SLC4A1 Gene Mutation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 945-945 ◽  
Author(s):  
Leo Kager ◽  
Lesley J Bruce ◽  
Joanna F Flatt ◽  
Petra Zeitlhofer ◽  
Gerhard Fritsch ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Conflicts Of Interest ◽  
Stop Codon ◽  
Disease Process ◽  
Failure To Thrive ◽  
Autosomal Recessive Inheritance ◽  
Band 3 ◽  
Southeast Asian ◽  
Heterozygous Mutation ◽  
Exon 11

Abstract The solute carrier 4A1 gene (SLC4A1) encodes theband 3 or bicarbonate anionic exchanger 1 (AE1). It is not only the major glycoprotein of the red blood cell (RBC) membrane but also expressed in acid secreting alpha-intercalated kidney cells. Functionally impairing SLC4A1 mutations reduce the expression and/or activity of AE1 thereby causing a unique combination of hemolytic anemia and distal renal tubular acidosis (dRTA). So far, only four such particular homozygote mutations have been documented in humans: an exon 11 p.400-408 deletion in Southeast Asian ovalocytosis (SAO) with transfusion-dependent dyserythropoietic anemia and dRTA (Picard et al, Blood 123:1963;2014), an exon 13 p.V488M mutation in transfusion-dependent hereditary spherocytosis (HS) and dRTA lacking band 3 (Ribeiro et al, Blood 96:1602;2000), an exon 16 p.S667F mutation in transfusion-dependent HS and incomplete dRTA (Toye et al, Blood 111:5380;2008), and finally an exon 19 p.Ala858Asp in a compensated hemolytic anemia with marked acanthocytosis, echinocytosis and dRTA (Fawaz et al, Europ J Haematol 88:350;2012). We report herein a novel homozygote variant in exon 12 in a patient with a transfusion-dependent dyserythropoietic/hemolytic anemia and complete dRTA. The now 4-years old Turkish boy was born after 32 weeks of gestation and presented with a severe hemolytic anemia (Hb 40 g/L) that required exchange transfusions and a complete dRTA that was treated with oral bicarbonate. He also suffered from delayed psychomotoric developmental with failure to thrive, trigonocephalus and strabismus convergens. Bone marrow smears showed marked dyserythropoiesis but normal myeloid and megakaryocytic lineages. Although necessary monthly transfusions impeded the patient's direct diagnostic work-up, a flow cytometric eosin-5-maleimide assay eventually revealed a reduced staining of his consanguine parents' and his two siblings' erythrocytes, who all had subclinical signs of spherocytosis despite normal RBC counts. Based on these findings, we analyzed the SLC4A1 gene and found two homozygous sequence variants in the patient, namely a novel disease-relevant exon 12 nonsense mutation c.1430C>A (p.Ser477X) and a disease-unrelated c.2312-48T>G (rs13306780). The ensuing stop codon of the former truncates the protein, prevents band 3 formation and reduces glycophorin A expression. Bright field imaging uncovered few phenotypic spherocytic band 3 null RBCs even in the peripheral blood. In accordance with the autosomal recessive inheritance pattern, both healthy parents as well as his healthy siblings were found to be heterozygous carriers. The band 3 protein was reduced to 50-60% in the parents' erythrocytes. An increased approximately 22 kDa-sized band was evident in Coomassie stained gels of the heterozygous mutation carriers' membrane preparations and classified by immunoblotting as peroxiredoxin 2 (PRDX2), which plays a major role in protecting RBCs from oxidative stress. Taken together, the provided data clearly confirm the relevance of this particular c.1430C>A (p.Ser477X) SLC4A1 mutation in the disease process. Of note, such a severe dyserythropoietic anemia and complete dRTA was also recently reported in a patient with Southeast Asian ovalocytosis and another form of homozygous SLC4A1 mutation (Picard et al, Blood 123:1963;2014). Disclosures No relevant conflicts of interest to declare.

scholarly journals Review of respiratory therapies in patients with spinal muscular atrophy

2018 ◽  
Vol 1 (1) ◽  
pp. 10-17
Author(s):  
V. Yu. Artemenko ◽  
E. V. Plotna
Keyword(s):  
Respiratory Failure ◽  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Sleep Disturbances ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Respiratory Muscles ◽  
Autosomal Recessive Inheritance ◽  
Severe Form ◽  
State Of Rest

The purpose of this article was to systematize available literary data and to provide general recommendations for respiratory therapy in patients with spinal muscular atrophy. Spinal muscular atrophy (SMA) is a severe neuromuscular disease with autosomal recessive inheritance with degeneration of alpha motor neurons in the anterior horns of the spinal cord, leading to progressive proximal muscle weakness and paralysis. SMN 1–2 genes potentially encode identical proteins, although most of the transcripts of the SMN1 genes are halfsized, whereas most transcripts of the SMN2 genes do not contain the seventh exon. Therefore, the SMN2 gene is only partially functional, and a low-level SMN protein is produced in SMA patients. Moreover, the number of copies of the SMN2 can not be considered an exact predictive factor for any particular patient. The main causes of mortality and deterioration in the quality of life are the development of secondary respiratory failure. Type 1 (a, b, c) is the heaviest: early onset and lack of motor abilities, usually patients with a disease of this type survive no more than 2 years. Type 2 – an intermediate type characterized by a later onset, the patient may take a sedentary position, survival may reach the adult height. Type 3 is the softest form that manifests itself at the age of 1 year, the patient can walk and stand. The forecast is more favorable. Type 4 “adult form” manifests itself at the age from 10 to 20 or from 20 to 30 years and has a favorable outlook. The main causes of respiratory failure in patients with neuromuscular diseases are weakness of the respiratory muscles, unproductive cough and sleep disturbances. The weakness of the respiratory muscles, defined as the inability of resting respiratory muscles in the state of rest to create a normal level of pressure and air flow velocity when entering and exhaling, is common. Patients with neuromuscular diseases are susceptible to sleep disruption, especially in the REM sleep phase, with the most frequent form of this disorder being hypoventilation. Over time, hypoventilation in a dream can become more prolonged, resulting in the development of a severe form of hypoxia, an increase in the level of carbon dioxide in the blood and the suppression of the activity of the respiratory center. Thus, as a result of the review of literary data, a strategy of respiratory support in patients with CMA was proposed.

scholarly journals A Novel Homozygous USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature

2021 ◽  
Author(s):  
ALPER GEZDIRICI ◽  
ÖZLEM KALAYCIK ŞENGÜL ◽  
MUSTAFA DOĞAN ◽  
BANU YILMAZ ÖZGÜVEN ◽  
EKREM AKBULUT
Keyword(s):  
Amino Acids ◽  
Splice Variant ◽  
Tertiary Structure ◽  
Stop Codon ◽  
Molecular Genetic ◽  
Autosomal Recessive Inheritance ◽  
Clinical Findings ◽  
Review Of The Literature ◽  
Whole Exome ◽  
Exon 1

Abstract Background: Hereditary cholestasis is a heterogeneous group of liver diseases that mostly show autosomal recessive inheritance. The phenotype of cholestasis is highly variable. Molecular genetic testing offers a useful approach to differentiate different types of cholestasis because some symptoms and findings overlap. Biallelic variants in USP53 have recently been reported in cholestasis phenotype. In this study we aim to characterize clinical findings and biological insights on a novel USP53 splice variant causing cholestasis phenotype and review of the literature. Methods and Results: We reported a novel splice variant (NM_019050.2:c.238-1G>C) in the USP53 gene via whole exome sequencing in a patient with cholestasis phenotype. This variant was confirmed by sanger sequencing and as a result of family segregation analysis; it was found to be a heterozygous state in the parents and the other healthy elder brother of our patient. According to in-silico analyses; the change in the splice region resulted in an increase in the length of exon 1, whereas the stop codon after the additional 3 amino acids (VTF) caused the protein to terminate prematurely. Thus, the mature USP53 protein, consisting of 1.073 amino acids, has been reduced to a small protein of 82 amino acids.Conclusions: We propose a model for the tertiary structure of USP53 for the first time, together with all these data, we support the association of biallelic variants of the USP53 gene with the cholestasis phenotype. We also presented a comparison of previously reported patients with the USP53-associated cholestasis phenotype to contribute to the literature.

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