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Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene...
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Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 84792

Special Issue Editors

Prof. Dr. Virginia Arechavala-Gomeza

E-Mail Website
Guest Editor
1. Neuromuscular Disorders Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
2. Ikerbasque, Basque Foundation for Science, Bilbao, Spain
Interests: antisense oligonucleotides; duchenne muscular dystrophy; myotonic dystrophy; outcome measures; dystrophin quantification
Dr. Lidia Gonzalez-Quereda

E-Mail Website
Guest Editor
CIBERER, IIB Sant Pau, 08025 Barcelona, Spain
Interests: molecular genetics; muscular dystrophies; congenital myopathies; next generation sequencing; transcriptome analysis

Special Issue Information

Dear Colleagues,

We would like to invite you to participate in this Special Issue, “Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy”.

More than 500 different disorders are included under the definition of neuromuscular disorders, and most of them are inherited diseases. In addition, these entities present a high clinical and genetic heterogeneity; in many cases, mutations in a single gene may be the cause of one or more neuromuscular disorders, while some disorders can be attributed to mutations in several genes. An ongoing revolution in diagnostic techniques has identified a large number of causative genes in the last two decades, and treatments are now being developed against these new targets.

The purpose of this Special Issue is to host research and review papers on our molecular understanding of neuromuscular disorders and associated genetic therapies. New results, confirmatory results, and contradictory results will also be considered for publication.

Prof. Virginia Arechavala-Gomeza
Dr. Lidia Gonzalez-Quereda
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Neuromuscular disorders
  • Gene therapy
  • Gene edition
  • RNA Therapies
  • Antisense oligonucleotides
  • Splicing
  • Massive Parallel Sequencing

Published Papers (16 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 180 KiB  
Editorial
Special Issue “Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy”
by Virginia Arechavala-Gomeza and Lidia Gonzalez-Quereda
Genes 2021, 12(2), 242; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020242 - 08 Feb 2021
Viewed by 1785
Abstract
Since the gene responsible for Duchenne muscular dystrophy was first described in 1987 [...] Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)

Research

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13 pages, 556 KiB  
Article
Circulating miR-206 as a Biomarker for Patients Affected by Severe Limb Girdle Muscle Dystrophies
by Valentina Pegoraro and Corrado Angelini
Genes 2021, 12(1), 85; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010085 - 12 Jan 2021
Cited by 10 | Viewed by 2158
Abstract
Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogeneous conditions, presenting with a wide clinical spectrum, leading to progressive proximal weakness caused by loss of muscle fibers. MiR-206 is a member of myomiRNAs, a group of miRNAs with important function in skeletal muscle. [...] Read more.
Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogeneous conditions, presenting with a wide clinical spectrum, leading to progressive proximal weakness caused by loss of muscle fibers. MiR-206 is a member of myomiRNAs, a group of miRNAs with important function in skeletal muscle. Our aim is to determine the value of miR-206 in detecting muscle disease evolution in patients affected by LGMD. We describe clinical features, disease history and progression of eleven patients affected by various types of LGMD: transportinopathy, sarcoglycanopathy and calpainopathy. We analyzed the patients’ mutations and we studied the circulating miR-206 in serum by qRT-PCR; muscle MRI was done with a 1.5 Tesla apparatus. The severe evolution of disease type is associated with the expression levels of miR-206, which was significantly elevated in our LGMD patient cohort in comparison with a control group. In particular, we observed an over-expression of miR-206 that was 50–80 folds elevated in two patients with a severe and early disease course in the transportinopathy and calpainopathy sub-types. The functional impairment was observed clinically and muscle loss and atrophy documented by muscle MRI. This study provides the first evidence that miR-206 is associated with phenotypic expression and it could be used as a prognostic indicator of LGMD disease progression. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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12 pages, 1777 KiB  
Article
FLNC Expression Level Influences the Activity of TEAD-YAP/TAZ Signaling
by Anastasia Knyazeva, Aleksandr Khudiakov, Raquel Vaz, Aleksey Muravyev, Ksenia Sukhareva, Thomas Sejersen and Anna Kostareva
Genes 2020, 11(11), 1343; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111343 - 13 Nov 2020
Cited by 6 | Viewed by 2452
Abstract
Filamin C (FLNC), being one of the major actin-binding proteins, is involved in the maintenance of key muscle cell functions. Inherited skeletal muscle and cardiac disorders linked to genetic variants in FLNC have attracted attention because of their high clinical importance and possibility [...] Read more.
Filamin C (FLNC), being one of the major actin-binding proteins, is involved in the maintenance of key muscle cell functions. Inherited skeletal muscle and cardiac disorders linked to genetic variants in FLNC have attracted attention because of their high clinical importance and possibility of genotype-phenotype correlations. To further expand on the role of FLNC in muscle cells, we focused on detailed alterations of muscle cell properties developed after the loss of FLNC. Using the CRISPR/Cas9 method we generated a C2C12 murine myoblast cell line with stably suppressed Flnc expression. FLNC-deficient myoblasts have a significantly higher proliferation rate combined with an impaired cell migration capacity. The suppression of Flnc expression leads to inability to complete myogenic differentiation, diminished expression of Myh1 and Myh4, alteration of transcriptional dynamics of myogenic factors, such as Mymk and Myog, and deregulation of Hippo signaling pathway. Specifically, we identified elevated basal levels of Hippo activity in myoblasts with loss of FLNC, and ineffective reduction of Hippo signaling activity during myogenic differentiation. The latter was restored by Flnc overexpression. In summary, we confirmed the role of FLNC in muscle cell proliferation, migration and differentiation, and demonstrated for the first time the direct link between Flnc expression and activity of TEAD-YAP\TAZ signaling. These findings support a role of FLNC in regulation of essential muscle processes relying on mechanical as well as signaling mechanisms. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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9 pages, 12422 KiB  
Article
Two New Cases of Hypertrophic Cardiomyopathy and Skeletal Muscle Features Associated with ALPK3 Homozygous and Compound Heterozygous Variants
by John Jorholt, Yulia Formicheva, Tatyana Vershinina, Artem Kiselev, Alexey Muravyev, Elena Demchenko, Petr Fedotov, Anna Zlotina, Anton Rygkov, Elena Vasichkina, Thomas Sejersen and Anna Kostareva
Genes 2020, 11(10), 1201; https://doi.org/10.3390/genes11101201 - 15 Oct 2020
Cited by 20 | Viewed by 2720
Abstract
Hypertrophic cardiomyopathy associated with damaging variants in the ALPK3 gene is a fairly recent discovery, and only a small number of patients have been described thus far. Here we present two additional patients with hypertrophic cardiomyopathy caused by biallelic variants in ALPK3. [...] Read more.
Hypertrophic cardiomyopathy associated with damaging variants in the ALPK3 gene is a fairly recent discovery, and only a small number of patients have been described thus far. Here we present two additional patients with hypertrophic cardiomyopathy caused by biallelic variants in ALPK3. Genetic investigation was performed using a targeted gene panel consisting of known cardiomyopathy-associated genes and whole exome sequencing. The patients showed a large difference in the age of onset, and both presented with extracardiac features that are often seen in ALPK3 patients. The patient with the later onset showed milder extracardiac symptoms, such as decreased muscle tone and distal muscular dystrophy, but had fast progression of cardiac complications leading to the need of heart transplantation. This study further elucidates the variability of both symptoms and age of onset among these patients. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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20 pages, 3281 KiB  
Article
LMNA Mutations G232E and R482L Cause Dysregulation of Skeletal Muscle Differentiation, Bioenergetics, and Metabolic Gene Expression Profile
by Elena V. Ignatieva, Oksana A. Ivanova, Margarita Y. Komarova, Natalia V. Khromova, Dmitrii E. Polev, Anna A. Kostareva, Alexey Sergushichev and Renata I. Dmitrieva
Genes 2020, 11(9), 1057; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11091057 - 07 Sep 2020
Cited by 10 | Viewed by 3683
Abstract
Laminopathies are a family of monogenic multi-system diseases resulting from mutations in the LMNA gene which include a wide range of neuromuscular disorders. Although lamins are expressed in most types of differentiated cells, LMNA mutations selectively affect only specific tissues by mechanisms that [...] Read more.
Laminopathies are a family of monogenic multi-system diseases resulting from mutations in the LMNA gene which include a wide range of neuromuscular disorders. Although lamins are expressed in most types of differentiated cells, LMNA mutations selectively affect only specific tissues by mechanisms that remain largely unknown. We have employed the combination of functional in vitro experiments and transcriptome analysis in order to determine how two LMNA mutations associated with different phenotypes affect skeletal muscle development and metabolism. We used a muscle differentiation model based on C2C12 mouse myoblasts genetically modified with lentivirus constructs bearing wild-type human LMNA (WT-LMNA) or R482L-LMNA/G232E-LMNA mutations, linked to familial partial lipodystrophy of the Dunnigan type and muscular dystrophy phenotype accordingly. We have shown that both G232E/R482L-LMNA mutations cause dysregulation in coordination of pathways that control cell cycle dynamics and muscle differentiation. We have also found that R482/G232E-LMNA mutations induce mitochondrial uncoupling and a decrease in glycolytic activity in differentiated myotubes. Both types of alterations may contribute to mutation-induced muscle tissue pathology. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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12 pages, 1798 KiB  
Article
Four Individuals with a Homozygous Mutation in Exon 1f of the PLEC Gene and Associated Myasthenic Features
by Magdalena Mroczek, Hacer Durmus, Ana Töpf, Yesim Parman and Volker Straub
Genes 2020, 11(7), 716; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11070716 - 27 Jun 2020
Cited by 10 | Viewed by 2873
Abstract
We identified the known c.1_9del mutation in the PLEC gene in four unrelated females from consanguineous families of Turkish origin. All individuals presented with slowly progressive limb-girdle weakness without any dermatological findings, and dystrophic changes observed in their muscle biopsies. Additionally, the neurological [...] Read more.
We identified the known c.1_9del mutation in the PLEC gene in four unrelated females from consanguineous families of Turkish origin. All individuals presented with slowly progressive limb-girdle weakness without any dermatological findings, and dystrophic changes observed in their muscle biopsies. Additionally, the neurological examination revealed ptosis, facial weakness, fatigability, and muscle cramps in all four cases. In two patients, repetitive nerve stimulation showed a borderline decrement and a high jitter was detected in all patients by single-fiber electromyography. Clinical improvement was observed after treatment with pyridostigmine and salbutamol was started. We further characterize the phenotype of patients with limb-girdle muscular dystrophy R17 clinically, by muscle magnetic resonance imaging (MRI) features and by describing a common 3.8 Mb haplotype in three individuals from the same geographical region. In addition, we review the neuromuscular symptoms associated with PLEC mutations and the role of plectin in the neuromuscular junction. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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13 pages, 750 KiB  
Article
Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain
by Lidia Gonzalez-Quereda, Maria Jose Rodriguez, Jordi Diaz-Manera, Jorge Alonso-Perez, Eduard Gallardo, Andres Nascimento, Carlos Ortez, Daniel Natera-de Benito, Montse Olive, Laura Gonzalez-Mera, Adolfo Lopez de Munain, Miren Zulaica, Juan Jose Poza, Ivonne Jerico, Laura Torne, Pau Riera, Jose Milisenda, Aurora Sanchez, Gloria Garrabou, Isabel Llano, Marcos Madruga-Garrido and Pia Gallanoadd Show full author list remove Hide full author list
Genes 2020, 11(5), 539; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11050539 - 11 May 2020
Cited by 25 | Viewed by 5354
Abstract
The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of [...] Read more.
The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN, NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients’ clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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23 pages, 783 KiB  
Article
Predominance of Dystrophinopathy Genotypes in Mexican Male Patients Presenting as Muscular Dystrophy with A Normal Multiplex Polymerase Chain Reaction DMD Gene Result: A Study Including Targeted Next-Generation Sequencing
by Miguel Angel Alcántara-Ortigoza, Miriam Erandi Reyna-Fabián, Ariadna González-del Angel, Bernardette Estandia-Ortega, Cesárea Bermúdez-López, Gabriela Marisol Cruz-Miranda and Matilde Ruíz-García
Genes 2019, 10(11), 856; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10110856 - 29 Oct 2019
Cited by 8 | Viewed by 3905
Abstract
The complete mutational spectrum of dystrophinopathies and limb-girdle muscular dystrophy (LGMD) remains unknown in Mexican population. Seventy-two unrelated Mexican male patients (73% of pediatric age) with clinical suspicion of muscular dystrophy and no evidence of DMD gene deletion on multiplex polymerase chain reaction [...] Read more.
The complete mutational spectrum of dystrophinopathies and limb-girdle muscular dystrophy (LGMD) remains unknown in Mexican population. Seventy-two unrelated Mexican male patients (73% of pediatric age) with clinical suspicion of muscular dystrophy and no evidence of DMD gene deletion on multiplex polymerase chain reaction (mPCR) analysis were analyzed by multiplex ligation-dependent probe amplification (MLPA). Those with a normal result were subjected to Sanger sequencing or to next-generation sequencing for DMD plus 10 selected LGMD-related genes. We achieved a diagnostic genotype in 80.5% (n = 58/72) of patients with predominance of dystrophinopathy-linked genotypes (68%, n = 49/72), followed by autosomal recessive LGMD-related genotypes (types 2A-R1, 2C-R5, 2E-R4, 2D-R3 and 2I-R9; 12.5%, n = 9/72). MLPA showed 4.2% of false-negatives for DMD deletions assessed by mPCR. Among the small DMD variants, 96.5% (n = 28/29) corresponded to null-alleles, most of which (72%) were inherited through a carrier mother. The FKRP p.[Leu276Ile]; [Asn463Asp] genotype is reported for the first time in Mexican patients as being associated with dilated cardiomyopathy. Absence of dysferlinopathies could be related to the small sample size and/or the predominantly pediatric age of patients. The employed strategy seems to be an affordable diagnosis approach for Mexican muscular dystrophy male patients and their families. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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15 pages, 1577 KiB  
Article
A Novel Missense Variant Associated with A Splicing Defect in A Myopathic Form of PGK1 Deficiency in The Spanish Population
by Virginia Garcia-Solaesa, Pablo Serrano-Lorenzo, Maria Antonia Ramos-Arroyo, Alberto Blázquez, Inmaculada Pagola-Lorz, Mercè Artigas-López, Joaquín Arenas, Miguel A. Martín and Ivonne Jericó-Pascual
Genes 2019, 10(10), 785; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10100785 - 10 Oct 2019
Cited by 11 | Viewed by 2552
Abstract
Phosphoglycerate kinase (PGK)1 deficiency is an X-linked inherited disease associated with different clinical presentations, sometimes as myopathic affectation without hemolytic anemia. We present a 40-year-old male with a mild psychomotor delay and mild mental retardation, who developed progressive exercise intolerance, cramps and sporadic [...] Read more.
Phosphoglycerate kinase (PGK)1 deficiency is an X-linked inherited disease associated with different clinical presentations, sometimes as myopathic affectation without hemolytic anemia. We present a 40-year-old male with a mild psychomotor delay and mild mental retardation, who developed progressive exercise intolerance, cramps and sporadic episodes of rhabdomyolysis but no hematological features. A genetic study was carried out by a next-generation sequencing (NGS) panel of 32 genes associated with inherited metabolic myopathies. We identified a missense variant in the PGK1 gene c.1114G > A (p.Gly372Ser) located in the last nucleotide of exon 9. cDNA studies demonstrated abnormalities in mRNA splicing because this change abolishes the exon 9 donor site. This novel variant is the first variant associated with a myopathic form of PGK1 deficiency in the Spanish population. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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Review

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30 pages, 6413 KiB  
Review
Antisense Transcription across Nucleotide Repeat Expansions in Neurodegenerative and Neuromuscular Diseases: Progress and Mysteries
by Ana F. Castro, Joana R. Loureiro, José Bessa and Isabel Silveira
Genes 2020, 11(12), 1418; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121418 - 27 Nov 2020
Cited by 9 | Viewed by 4382
Abstract
Unstable repeat expansions and insertions cause more than 30 neurodegenerative and neuromuscular diseases. Remarkably, bidirectional transcription of repeat expansions has been identified in at least 14 of these diseases. More remarkably, a growing number of studies has been showing that both sense and [...] Read more.
Unstable repeat expansions and insertions cause more than 30 neurodegenerative and neuromuscular diseases. Remarkably, bidirectional transcription of repeat expansions has been identified in at least 14 of these diseases. More remarkably, a growing number of studies has been showing that both sense and antisense repeat RNAs are able to dysregulate important cellular pathways, contributing together to the observed clinical phenotype. Notably, antisense repeat RNAs from spinocerebellar ataxia type 7, myotonic dystrophy type 1, Huntington’s disease and frontotemporal dementia/amyotrophic lateral sclerosis associated genes have been implicated in transcriptional regulation of sense gene expression, acting either at a transcriptional or posttranscriptional level. The recent evidence that antisense repeat RNAs could modulate gene expression broadens our understanding of the pathogenic pathways and adds more complexity to the development of therapeutic strategies for these disorders. In this review, we cover the amazing progress made in the understanding of the pathogenic mechanisms associated with repeat expansion neurodegenerative and neuromuscular diseases with a focus on the impact of antisense repeat transcription in the development of efficient therapies. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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27 pages, 1865 KiB  
Review
An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
by Andrea López-Martínez, Patricia Soblechero-Martín, Laura de-la-Puente-Ovejero, Gisela Nogales-Gadea and Virginia Arechavala-Gomeza
Genes 2020, 11(9), 1109; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11091109 - 22 Sep 2020
Cited by 57 | Viewed by 9401
Abstract
Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy, caused by expansion of a CTG triplet repeat in the 3′ untranslated region (3′UTR) of the myotonic dystrophy protein kinase (DMPK) gene. The pathological CTG repeats result [...] Read more.
Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy, caused by expansion of a CTG triplet repeat in the 3′ untranslated region (3′UTR) of the myotonic dystrophy protein kinase (DMPK) gene. The pathological CTG repeats result in protein trapping by expanded transcripts, a decreased DMPK translation and the disruption of the chromatin structure, affecting neighboring genes expression. The muscleblind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) are two families of tissue-specific regulators of developmentally programmed alternative splicing that act as antagonist regulators of several pre-mRNA targets, including troponin 2 (TNNT2), insulin receptor (INSR), chloride channel 1 (CLCN1) and MBNL2. Sequestration of MBNL proteins and up-regulation of CELF1 are key to DM1 pathology, inducing a spliceopathy that leads to a developmental remodelling of the transcriptome due to an adult-to-foetal splicing switch, which results in the loss of cell function and viability. Moreover, recent studies indicate that additional pathogenic mechanisms may also contribute to disease pathology, including a misregulation of cellular mRNA translation, localization and stability. This review focuses on the cause and effects of MBNL and CELF1 deregulation in DM1, describing the molecular mechanisms underlying alternative splicing misregulation for a deeper understanding of DM1 complexity. To contribute to this analysis, we have prepared a comprehensive list of transcript alterations involved in DM1 pathogenesis, as well as other deregulated mRNA processing pathways implications. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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25 pages, 1133 KiB  
Review
Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update
by Chengmei Sun, Luoan Shen, Zheng Zhang and Xin Xie
Genes 2020, 11(8), 837; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11080837 - 23 Jul 2020
Cited by 81 | Viewed by 22841
Abstract
Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked [...] Read more.
Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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17 pages, 543 KiB  
Review
Cardiac Involvement in Dystrophin-Deficient Females: Current Understanding and Implications for the Treatment of Dystrophinopathies
by Kenji Rowel Q. Lim, Narin Sheri, Quynh Nguyen and Toshifumi Yokota
Genes 2020, 11(7), 765; https://doi.org/10.3390/genes11070765 - 08 Jul 2020
Cited by 22 | Viewed by 6480
Abstract
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive condition caused primarily by out-of-frame mutations in the dystrophin gene. In males, DMD presents with progressive body-wide muscle deterioration, culminating in death as a result of cardiac or respiratory failure. A milder form of [...] Read more.
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive condition caused primarily by out-of-frame mutations in the dystrophin gene. In males, DMD presents with progressive body-wide muscle deterioration, culminating in death as a result of cardiac or respiratory failure. A milder form of DMD exists, called Becker muscular dystrophy (BMD), which is typically caused by in-frame dystrophin gene mutations. It should be emphasized that DMD and BMD are not exclusive to males, as some female dystrophin mutation carriers do present with similar symptoms, generally at reduced levels of severity. Cardiac involvement in particular is a pressing concern among manifesting females, as it may develop into serious heart failure or could predispose them to certain risks during pregnancy or daily life activities. It is known that about 8% of carriers present with dilated cardiomyopathy, though it may vary from 0% to 16.7%, depending on if the carrier is classified as having DMD or BMD. Understanding the genetic and molecular mechanisms underlying cardiac manifestations in dystrophin-deficient females is therefore of critical importance. In this article, we review available information from the literature on this subject, as well as discuss the implications of female carrier studies on the development of therapies aiming to increase dystrophin levels in the heart. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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14 pages, 648 KiB  
Review
CRISPR-Generated Animal Models of Duchenne Muscular Dystrophy
by Kenji Rowel Q. Lim, Quynh Nguyen, Kasia Dzierlega, Yiqing Huang and Toshifumi Yokota
Genes 2020, 11(3), 342; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11030342 - 24 Mar 2020
Cited by 14 | Viewed by 7743
Abstract
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disorder most commonly caused by mutations disrupting the reading frame of the dystrophin (DMD) gene. DMD codes for dystrophin, which is critical for maintaining the integrity of muscle cell membranes. Without [...] Read more.
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disorder most commonly caused by mutations disrupting the reading frame of the dystrophin (DMD) gene. DMD codes for dystrophin, which is critical for maintaining the integrity of muscle cell membranes. Without dystrophin, muscle cells receive heightened mechanical stress, becoming more susceptible to damage. An active body of research continues to explore therapeutic treatments for DMD as well as to further our understanding of the disease. These efforts rely on having reliable animal models that accurately recapitulate disease presentation in humans. While current animal models of DMD have served this purpose well to some extent, each has its own limitations. To help overcome this, clustered regularly interspaced short palindromic repeat (CRISPR)-based technology has been extremely useful in creating novel animal models for DMD. This review focuses on animal models developed for DMD that have been created using CRISPR, their advantages and disadvantages as well as their applications in the DMD field. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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Other

8 pages, 946 KiB  
Brief Report
Preliminary Findings on CTG Expansion Determination in Different Tissues from Patients with Myotonic Dystrophy Type 1
by Alfonsina Ballester-Lopez, Emma Koehorst, Ian Linares-Pardo, Judit Núñez-Manchón, Miriam Almendrote, Giuseppe Lucente, Andrea Arbex, Carles Puente, Alejandro Lucia, Darren G. Monckton, Sarah A. Cumming, Guillem Pintos-Morell, Jaume Coll-Cantí, Alba Ramos-Fransi, Alicia Martínez-Piñeiro and Gisela Nogales-Gadea
Genes 2020, 11(11), 1321; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111321 - 07 Nov 2020
Cited by 4 | Viewed by 2215
Abstract
Myotonic Dystrophy type 1 (DM1) is characterized by a high genetic and clinical variability. Determination of the genetic variability in DM1 might help to determine whether there is an association between CTG (Cytosine-Thymine-Guanine) expansion and the clinical manifestations of this condition. We studied [...] Read more.
Myotonic Dystrophy type 1 (DM1) is characterized by a high genetic and clinical variability. Determination of the genetic variability in DM1 might help to determine whether there is an association between CTG (Cytosine-Thymine-Guanine) expansion and the clinical manifestations of this condition. We studied the variability of the CTG expansion (progenitor, mode, and longest allele, respectively, and genetic instability) in three tissues (blood, muscle, and tissue) from eight patients with DM1. We also studied the association of genetic data with the patients’ clinical characteristics. Although genetic instability was confirmed in all the tissues that we studied, our results suggest that CTG expansion is larger in muscle and skin cells compared with peripheral blood leukocytes. While keeping in mind that more research is needed in larger cohorts, we have provided preliminary evidence suggesting that the estimated progenitor CTG size in muscle could be potentially used as an indicator of age of disease onset and muscle function impairment. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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Brief Report
The Need for Establishing a Universal CTG Sizing Method in Myotonic Dystrophy Type 1
by Alfonsina Ballester-Lopez, Ian Linares-Pardo, Emma Koehorst, Judit Núñez-Manchón, Guillem Pintos-Morell, Jaume Coll-Cantí, Miriam Almendrote, Giuseppe Lucente, Andrea Arbex, Jonathan J. Magaña, Nadia M. Murillo-Melo, Alejandro Lucia, Darren G. Monckton, Sarah A. Cumming, Alba Ramos-Fransi, Alicia Martínez-Piñeiro and Gisela Nogales-Gadea
Genes 2020, 11(7), 757; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11070757 - 07 Jul 2020
Cited by 5 | Viewed by 2710
Abstract
The number of cytosine-thymine-guanine (CTG) repeats (‘CTG expansion size’) in the 3′untranslated region (UTR) region of the dystrophia myotonica-protein kinase (DMPK) gene is a hallmark of myotonic dystrophy type 1 (DM1), which has been related to age of disease onset [...] Read more.
The number of cytosine-thymine-guanine (CTG) repeats (‘CTG expansion size’) in the 3′untranslated region (UTR) region of the dystrophia myotonica-protein kinase (DMPK) gene is a hallmark of myotonic dystrophy type 1 (DM1), which has been related to age of disease onset and clinical severity. However, accurate determination of CTG expansion size is challenging due to its characteristic instability. We compared five different approaches (heat pulse extension polymerase chain reaction [PCR], long PCR-Southern blot [with three different primers sets—1, 2 and 3] and small pool [SP]-PCR) to estimate CTG expansion size in the progenitor allele as well as the most abundant CTG expansion size, in 15 patients with DM1. Our results indicated variability between the methods (although we found no overall differences between long PCR 1 and 2 and SP-PCR, respectively). While keeping in mind the limited sample size of our patient cohort, SP-PCR appeared as the most suitable technique, with an inverse significant correlation found between CTG expansion size of the progenitor allele, as determined by this method, and age of disease onset (r = −0.734, p = 0.016). Yet, in light of the variability of the results obtained with the different methods, we propose that an international agreement is needed to determine which is the most suitable method for assessing CTG expansion size in DM1. Full article
(This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy)
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