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10 pages, 1858 KiB

Open AccessArticle

Evaluation of Mean Percentage of Full-Length SMN Transcripts as a Molecular Biomarker of Spinal Muscular Atrophy

by Marianna Maretina, Anna Egorova, Kristina Lanko, Vladislav Baranov and Anton Kiselev

Genes 2022, 13(10), 1911; https://doi.org/10.3390/genes13101911 - 20 Oct 2022

Cited by 3 | Viewed by 1577

Abstract

The elevation of SMN transcript and protein level remains the principal aim of SMA therapy. Still, there is no standard molecular biomarker for the assessment of its efficacy. In the current study, we tested three methods of SMN transcript level measurement using real-time [...] Read more.

The elevation of SMN transcript and protein level remains the principal aim of SMA therapy. Still, there is no standard molecular biomarker for the assessment of its efficacy. In the current study, we tested three methods of SMN transcript level measurement using real-time RT-PCR, quantitative fluorescent RT-PCR, and a semiquantitative RT-PCR gel densitometric assay. We examined several potential mRNA-based biomarkers and examined their sensitivity and reliability by comparing the obtained values in peripheral blood mononuclear cells of SMA patients, SMA carriers, and healthy individuals. We found that the mean percentage of full-length (FL-SMN) transcripts relative to the total sum of FL-SMN and exon 7-deleted (Δ7 SMN) transcripts detected by semiquantitative and quantitative fluorescence RT-PCR differed significantly between the three analyzed groups. The relevance of this biomarker was proven in an SMN2-targeting therapeutic experiment. We showed that the values of the biomarker changed significantly in SMA fibroblast cell cultures after treatment with therapeutic antisense oligonucleotides targeting the ISS-N1 site in intron 7 of the SMN2 gene. The obtained results indicate the convenience of using the mean percentage of FL-SMN transcripts determined by semiquantitative and quantitative fluorescence RT-PCR as a putative biomarker for the assessment of SMA therapy efficacy in vitro. Full article

(This article belongs to the Special Issue Genetics of Muscular Disorders)

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9 pages, 1309 KiB

Open AccessArticle

Novel Exon-Skipping Therapeutic Approach for the DMD Gene Based on Asymptomatic Deletions of Exon 49

by Mario Abaji, Svetlana Gorokhova, Nathalie Da Silva, Tiffany Busa, Maude Grelet, Chantal Missirian, Sabine Sigaudy, Nicole Philip, France Leturcq, Nicolas Lévy, Martin Krahn and Marc Bartoli

Genes 2022, 13(7), 1277; https://doi.org/10.3390/genes13071277 - 19 Jul 2022

Cited by 2 | Viewed by 2618

Abstract

Exon skipping is a promising therapeutic approach. One important condition for this approach is that the exon-skipped form of the gene can at least partially perform the required function and lead to improvement of the phenotype. It is therefore critical to identify the [...] Read more.

Exon skipping is a promising therapeutic approach. One important condition for this approach is that the exon-skipped form of the gene can at least partially perform the required function and lead to improvement of the phenotype. It is therefore critical to identify the exons that can be skipped without a significant deleterious effect on the protein function. Pathogenic variants in the DMD gene are responsible for Duchenne muscular dystrophy (DMD). We report for the first time a deletion of the in-frame exon 49 associated with a strikingly normal muscular phenotype. Based on this observation, and on previously known therapeutic approaches using exon skipping in DMD for other single exons, we aimed to extend the clinical use of exon skipping for patients carrying truncating mutations in exon 49. We first determined the precise genomic position of the exon 49 deletion in our patients. We then demonstrated the feasibility of skipping exon 49 using an in vitro AON (antisense oligonucleotide) approach in human myotubes carrying a truncating pathogenic variant as well as in healthy ones. This work is a proof of concept aiming to expand exon-skipping approaches for DMD exon 49. Full article

(This article belongs to the Special Issue Genetics of Muscular Disorders)

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15 pages, 1276 KiB

Open AccessFeature PaperArticle

Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population

by Mathieu Cerino, Patricio González-Hormazábal, Mario Abaji, Sebastien Courrier, Francesca Puppo, Yves Mathieu, Alejandra Trangulao, Nicholas Earle, Claudia Castiglioni, Jorge Díaz, Mario Campero, Ricardo Hughes, Carmen Vargas, Rocío Cortés, Karin Kleinsteuber, Ignacio Acosta, J. Andoni Urtizberea, Nicolas Lévy, Marc Bartoli, Martin Krahn, Lilian Jara, Pablo Caviedes, Svetlana Gorokhova and Jorge A. Bevilacqua Show full author list Hide full author list

Genes 2022, 13(6), 1076; https://doi.org/10.3390/genes13061076 - 16 Jun 2022

Cited by 4 | Viewed by 2405

Abstract

Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with [...] Read more.

Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy. Full article

(This article belongs to the Special Issue Genetics of Muscular Disorders)

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14 pages, 1544 KiB

Open AccessArticle

Estrogen Receptor Type 1 and Type 2 Presence in Paravertebral Skeletal Muscles: Expression Level and Relation to Phenotype in Children with Idiopathic Scoliosis

by Tomasz Kotwicki, Marek Tomaszewski, Mirosław Andrusiewicz, Aleksandra Śliwa, Błażej Rusin and Małgorzata Kotwicka

Genes 2022, 13(5), 739; https://doi.org/10.3390/genes13050739 - 22 Apr 2022

Cited by 5 | Viewed by 2169

Abstract

The study aimed to detect the presence and assess the expression levels of the estrogen receptors type 1 (ESR1) and type 2 (ESR2) within paravertebral skeletal muscles of female patients with idiopathic scoliosis (IS) in relation to phenotype parameters. Intraoperatively, the muscle samples [...] Read more.

The study aimed to detect the presence and assess the expression levels of the estrogen receptors type 1 (ESR1) and type 2 (ESR2) within paravertebral skeletal muscles of female patients with idiopathic scoliosis (IS) in relation to phenotype parameters. Intraoperatively, the muscle samples were obtained from 35 adolescent females. The RT-qPCR, western blot and immunohistochemistry techniques were applied. The ESR1 and ESR2 were detected within paravertebral skeletal muscle cells, either the superficial or the deep ones. The ESR1 expression level was significantly higher in the deep muscles compared to the superficial ones. A left-right asymmetry of the ESR1 and ESR2 expression level was demonstrated in the deep muscles. There was a significant relationship between the expression asymmetry and either the Cobb angle or the progression risk factor: both parameters decreased to the smallest values in the case of symmetric ESR1 or ESR2 expression, while they increased with increasing expression asymmetry. In conclusion, the ESR1 and ESR2 presence was confirmed in skeletal paravertebral muscles of patients with idiopathic scoliosis. The increased expression level and asymmetry of estrogen receptors in deep skeletal muscles was related to increasing scoliotic deformity magnitude or increasing risk of deformity deterioration. These findings may highlight the etiopathogenesis of IS in children. Full article

(This article belongs to the Special Issue Genetics of Muscular Disorders)

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7 pages, 780 KiB

Open AccessArticle

A National French Consensus on Gene List for the Diagnosis of Charcot–Marie–Tooth Disease and Related Disorders Using Next-Generation Sequencing

by Thibaut Benquey, Emmanuelle Pion, Mireille Cossée, Martin Krahn, Tanya Stojkovic, Aurélien Perrin, Mathieu Cerino, Annamaria Molon, Anne-Sophie Lia, Corinne Magdelaine, Bruno Francou, Anne Guiochon-Mantel, Marie-Claire Malinge, Eric Leguern, Nicolas Lévy, Shahram Attarian, Philippe Latour and Nathalie Bonello-Palot

Genes 2022, 13(2), 318; https://doi.org/10.3390/genes13020318 - 9 Feb 2022

Cited by 4 | Viewed by 2018

Abstract

Next generation sequencing (NGS) is strategically used for genetic diagnosis in patients with Charcot–Marie–Tooth disease (CMT) and related disorders called non-syndromic inherited peripheral neuropathies (NSIPN) in this paper. With over 100 different CMT-associated genes involved and ongoing discoveries, an important interlaboratory diversity of [...] Read more.

Next generation sequencing (NGS) is strategically used for genetic diagnosis in patients with Charcot–Marie–Tooth disease (CMT) and related disorders called non-syndromic inherited peripheral neuropathies (NSIPN) in this paper. With over 100 different CMT-associated genes involved and ongoing discoveries, an important interlaboratory diversity of gene panels exists at national and international levels. Here, we present the work of the French National Network for Rare Neuromuscular Diseases (FILNEMUS) genetic diagnosis section which coordinates the seven French diagnosis laboratories using NGS for peripheral neuropathies. This work aimed to establish a unique, simple and accurate gene classification based on literature evidence. In NSIPN, three subgroups were usually distinguished: (1) HMSN, Hereditary Motor Sensory Neuropathy, (2) dHMN, distal Hereditary Motor Neuropathy, and (3) HSAN, Hereditary Sensory Autonomic Neuropathy. First, we reported ClinGen evaluation, and second, for the genes not evaluated yet by ClinGen, we classified them as “definitive” if reported in at least two clinical publications and associated with one report of functional evidence, or “limited” otherwise. In total, we report a unique consensus gene list for NSIPN including the three subgroups with 93 genes definitive and 34 limited, which is a good rate for our gene’s panel for molecular diagnostic use. Full article

(This article belongs to the Special Issue Genetics of Muscular Disorders)

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Review

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11 pages, 1042 KiB

Open AccessReview

Current and Future Approaches to Classify VUSs in LGMD-Related Genes

by Chengcheng Li, Gabe Haller and Conrad C. Weihl

Genes 2022, 13(2), 382; https://doi.org/10.3390/genes13020382 - 19 Feb 2022

Cited by 3 | Viewed by 2130

Abstract

Next-generation sequencing (NGS) has revealed large numbers of genetic variants in LGMD-related genes, with most of them classified as variants of uncertain significance (VUSs). VUSs are genetic changes with unknown pathological impact and present a major challenge in genetic test interpretation and disease [...] Read more.

Next-generation sequencing (NGS) has revealed large numbers of genetic variants in LGMD-related genes, with most of them classified as variants of uncertain significance (VUSs). VUSs are genetic changes with unknown pathological impact and present a major challenge in genetic test interpretation and disease diagnosis. Understanding the phenotypic consequences of VUSs can provide clinical guidance regarding LGMD risk and therapy. In this review, we provide a brief overview of the subtypes of LGMD, disease diagnosis, current classification systems for investigating VUSs, and a potential deep mutational scanning approach to classify VUSs in LGMD-related genes. Full article

(This article belongs to the Special Issue Genetics of Muscular Disorders)

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18 pages, 328 KiB

Open AccessReview

Myotonic Dystrophies: A Genetic Overview

by Payam Soltanzadeh

Genes 2022, 13(2), 367; https://doi.org/10.3390/genes13020367 - 17 Feb 2022

Cited by 11 | Viewed by 5017

Abstract

Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, which can affect other non-skeletal muscle organs such as the heart, brain and gastrointestinal system. There are two genetically distinct types of myotonic dystrophy: myotonic dystrophy type 1 (DM1) and myotonic dystrophy [...] Read more.

Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, which can affect other non-skeletal muscle organs such as the heart, brain and gastrointestinal system. There are two genetically distinct types of myotonic dystrophy: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), both dominantly inherited with significant overlap in clinical manifestations. DM1 results from CTG repeat expansions in the 3′-untranslated region (3′UTR) of the DMPK (dystrophia myotonica protein kinase) gene on chromosome 19, while DM2 is caused by CCTG repeat expansions in intron 1 of the CNBP (cellular nucleic acid-binding protein) gene on chromosome 3. Recent advances in genetics and molecular biology, especially in the field of RNA biology, have allowed better understanding of the potential pathomechanisms involved in DM. In this review article, core clinical features and genetics of DM are presented followed by a discussion on the current postulated pathomechanisms and therapeutic approaches used in DM, including the ones currently in human clinical trial phase. Full article

(This article belongs to the Special Issue Genetics of Muscular Disorders)

17 pages, 638 KiB

Open AccessEditor’s ChoiceReview

Antisense and Gene Therapy Options for Duchenne Muscular Dystrophy Arising from Mutations in the N-Terminal Hotspot

by Harry Wilton-Clark and Toshifumi Yokota

Genes 2022, 13(2), 257; https://doi.org/10.3390/genes13020257 - 28 Jan 2022

Cited by 16 | Viewed by 6054

Abstract

Duchenne muscular dystrophy (DMD) is a fatal genetic disease affecting children that is caused by a mutation in the gene encoding for dystrophin. In the absence of functional dystrophin, patients experience progressive muscle deterioration, leaving them wheelchair-bound by age 12 and with few [...] Read more.

Duchenne muscular dystrophy (DMD) is a fatal genetic disease affecting children that is caused by a mutation in the gene encoding for dystrophin. In the absence of functional dystrophin, patients experience progressive muscle deterioration, leaving them wheelchair-bound by age 12 and with few patients surviving beyond their third decade of life as the disease advances and causes cardiac and respiratory difficulties. In recent years, an increasing number of antisense and gene therapies have been studied for the treatment of muscular dystrophy; however, few of these therapies focus on treating mutations arising in the N-terminal encoding region of the dystrophin gene. This review summarizes the current state of development of N-terminal antisense and gene therapies for DMD, mainly focusing on exon-skipping therapy for duplications and deletions, as well as microdystrophin therapy. Full article

(This article belongs to the Special Issue Genetics of Muscular Disorders)

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4 pages, 204 KiB

Open AccessPerspective

The Contribution of Genetics to Muscle Disuse, Retraining, and Aging

by Giuseppe Sirago, Anna Picca, Emiliana Giacomello, Emanuele Marzetti and Luana Toniolo

Genes 2022, 13(8), 1378; https://doi.org/10.3390/genes13081378 - 1 Aug 2022

Cited by 6 | Viewed by 1454

Abstract

Genetic background may partly explain differences in muscle responses to internal or external stimuli. Muscle disuse involves various degrees of skeletal muscle atrophy due to inactivity and mechanical unloading. Whether and to which extent genetic background impacts disuse atrophy and retraining in individuals [...] Read more.

Genetic background may partly explain differences in muscle responses to internal or external stimuli. Muscle disuse involves various degrees of skeletal muscle atrophy due to inactivity and mechanical unloading. Whether and to which extent genetic background impacts disuse atrophy and retraining in individuals of different ages are currently unclear. Here, we provide a brief overview of relevant literature on the contribution of genetics to muscle disuse, retraining, and aging, and offer a perspective on unanswered questions on the subject that may open new venues for research. Full article

(This article belongs to the Special Issue Genetics of Muscular Disorders)

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14 pages, 2414 KiB

Open AccessProtocol

A Novel Method for Detecting Duchenne Muscular Dystrophy in Blood Serum of mdx Mice

by Nicole M. Ralbovsky, Paromita Dey, Andrew Galfano, Bijan K. Dey and Igor K. Lednev

Genes 2022, 13(8), 1342; https://doi.org/10.3390/genes13081342 - 27 Jul 2022

Cited by 1 | Viewed by 1403

Abstract

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy, typically affecting males in infancy. The disease causes progressive weakness and atrophy of skeletal muscles, with approximately 20,000 new cases diagnosed yearly. Currently, methods for diagnosing DMD are invasive, laborious, and [...] Read more.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy, typically affecting males in infancy. The disease causes progressive weakness and atrophy of skeletal muscles, with approximately 20,000 new cases diagnosed yearly. Currently, methods for diagnosing DMD are invasive, laborious, and unable to make accurate early detections. While there is no cure for DMD, there are limited treatments available for managing symptoms. As such, there is a crucial unmet need to develop a simple and non-invasive method for accurately detecting DMD as early as possible. Raman spectroscopy with chemometric analysis is shown to have the potential to fill this diagnostic need. Full article

(This article belongs to the Special Issue Genetics of Muscular Disorders)

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