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The Genetic and Molecular Basis of Congenital Myopathies and Various Rare Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 14658

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Special Issue Editor

Dr. Pankaj Agrawal

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Guest Editor

Merton Bernfield Chair in Newborn Medcine, Department of Pediatrics, Boston Children’s Hospital, and Associate Professor of Pediatrcis, Harvard Medical School, Boston, MA, USA
Interests: genetic and molecular basis of congenital myopathies and various rare diseases

Special Issue Information

Dear Colleagues,

The genetic and molecular bases of congenital myopathies and various rare diseases are becoming more and more defined, but many patients with by these conditions continue to remain undiagnosed. Congenital myopathies are a diverse group of diseases, examples of which include nemaline, centronuclear, myotubular myopathies. There is significant overlap in the genetic basis of these conditions; for example, ryanodine (RYR1) mutations can cause centronuclear myopathy, nemaline myopathy, multiminicore disease, and central core disease. With the recent advances in the development of targeted therapies, it is critical to understand the molecular determinants of these conditions. Recent efforts at a gene therapy approach against myotubular myopathy is an example of the possible development of specific therapies. Similarly, for various rare and ultrarare conditions, the elucidation of their genetic and molecular bases will be critical to understanding those disorders at the molecular level and to developing specific therapies. Contributions to this Special Issue will provide new insights into this critical area of research.

Dr. Pankaj Agrawal
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

Congenital myopathies
rare diseases
Genetics

Published Papers (4 papers)

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Research

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15 pages, 2128 KiB

Open AccessArticle

microRNA-mRNA Profile of Skeletal Muscle Differentiation and Relevance to Congenital Myotonic Dystrophy

by Sarah U. Morton, Christopher R. Sefton, Huanqing Zhang, Manhong Dai, David L. Turner, Michael D. Uhler and Pankaj B. Agrawal

Int. J. Mol. Sci. 2021, 22(5), 2692; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052692 - 07 Mar 2021

Cited by 6 | Viewed by 2372

Abstract

microRNAs (miRNAs) regulate messenger RNA (mRNA) abundance and translation during key developmental processes including muscle differentiation. Assessment of miRNA targets can provide insight into muscle biology and gene expression profiles altered by disease. mRNA and miRNA libraries were generated from C2C12 myoblasts during differentiation, and predicted miRNA targets were identified based on presence of miRNA binding sites and reciprocal expression. Seventeen miRNAs were differentially expressed at all time intervals (comparing days 0, 2, and 5) of differentiation. mRNA targets of differentially expressed miRNAs were enriched for functions related to calcium signaling and sarcomere formation. To evaluate this relationship in a disease state, we evaluated the miRNAs differentially expressed in human congenital myotonic dystrophy (CMD) myoblasts and compared with normal control. Seventy-four miRNAs were differentially expressed during healthy human myocyte maturation, of which only 12 were also up- or downregulated in CMD patient cells. The 62 miRNAs that were only differentially expressed in healthy cells were compared with differentiating C2C12 cells. Eighteen of the 62 were conserved in mouse and up- or down-regulated during mouse myoblast differentiation, and their C2C12 targets were enriched for functions related to muscle differentiation and contraction. Full article

(This article belongs to the Special Issue The Genetic and Molecular Basis of Congenital Myopathies and Various Rare Diseases)

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Review

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16 pages, 2690 KiB

Open AccessReview

Troponin Variants in Congenital Myopathies: How They Affect Skeletal Muscle Mechanics

by Martijn van de Locht, Tamara C. Borsboom, Josine M. Winter and Coen A. C. Ottenheijm

Int. J. Mol. Sci. 2021, 22(17), 9187; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179187 - 25 Aug 2021

Cited by 7 | Viewed by 4186

Abstract

The troponin complex is a key regulator of muscle contraction. Multiple variants in skeletal troponin encoding genes result in congenital myopathies. TNNC2 has been implicated in a novel congenital myopathy, TNNI2 and TNNT3 in distal arthrogryposis (DA), and TNNT1 and TNNT3 in nemaline myopathy (NEM). Variants in skeletal troponin encoding genes compromise sarcomere function, e.g., by altering the Ca²⁺ sensitivity of force or by inducing atrophy. Several potential therapeutic strategies are available to counter the effects of variants, such as troponin activators, introduction of wild-type protein through AAV gene therapy, and myosin modulation to improve muscle contraction. The mechanisms underlying the pathophysiological effects of the variants in skeletal troponin encoding genes are incompletely understood. Furthermore, limited knowledge is available on the structure of skeletal troponin. This review focusses on the physiology of slow and fast skeletal troponin and the pathophysiology of reported variants in skeletal troponin encoding genes. A better understanding of the pathophysiological effects of these variants, together with enhanced knowledge regarding the structure of slow and fast skeletal troponin, will direct the development of treatment strategies. Full article

(This article belongs to the Special Issue The Genetic and Molecular Basis of Congenital Myopathies and Various Rare Diseases)

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16 pages, 2135 KiB

Open AccessReview

Inherited Defects of the ASC-1 Complex in Congenital Neuromuscular Diseases

by Justine Meunier, Rocio-Nur Villar-Quiles, Isabelle Duband-Goulet and Ana Ferreiro

Int. J. Mol. Sci. 2021, 22(11), 6039; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116039 - 03 Jun 2021

Cited by 6 | Viewed by 3395

Abstract

Defects in transcriptional and cell cycle regulation have emerged as novel pathophysiological mechanisms in congenital neuromuscular disease with the recent identification of mutations in the TRIP4 and ASCC1 genes, encoding, respectively, ASC-1 and ASCC1, two subunits of the ASC-1 (Activating Signal Cointegrator-1) complex. This complex is a poorly known transcriptional coregulator involved in transcriptional, post-transcriptional or translational activities. Inherited defects in components of the ASC-1 complex have been associated with several autosomal recessive phenotypes, including severe and mild forms of striated muscle disease (congenital myopathy with or without myocardial involvement), but also cases diagnosed of motor neuron disease (spinal muscular atrophy). Additionally, antenatal bone fractures were present in the reported patients with ASCC1 mutations. Functional studies revealed that the ASC-1 subunit is a novel regulator of cell cycle, proliferation and growth in muscle and non-muscular cells. In this review, we summarize and discuss the available data on the clinical and histopathological phenotypes associated with inherited defects of the ASC-1 complex proteins, the known genotype–phenotype correlations, the ASC-1 pathophysiological role, the puzzling question of motoneuron versus primary muscle involvement and potential future research avenues, illustrating the study of rare monogenic disorders as an interesting model paradigm to understand major physiological processes. Full article

(This article belongs to the Special Issue The Genetic and Molecular Basis of Congenital Myopathies and Various Rare Diseases)

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13 pages, 5824 KiB

Open AccessReview

Striated Preferentially Expressed Protein Kinase (SPEG) in Muscle Development, Function, and Disease

by Shiyu Luo, Samantha M. Rosen, Qifei Li and Pankaj B. Agrawal

Int. J. Mol. Sci. 2021, 22(11), 5732; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115732 - 27 May 2021

Cited by 10 | Viewed by 3712

Abstract

Mutations in striated preferentially expressed protein kinase (SPEG), a member of the myosin light chain kinase protein family, are associated with centronuclear myopathy (CNM), cardiomyopathy, or a combination of both. Burgeoning evidence suggests that SPEG plays critical roles in the development, maintenance, and function of skeletal and cardiac muscles. Here we review the genotype-phenotype relationships and the molecular mechanisms of SPEG-related diseases. This review will focus on the progress made toward characterizing SPEG and its interacting partners, and its multifaceted functions in muscle regeneration, triad development and maintenance, and excitation-contraction coupling. We will also discuss future directions that are yet to be investigated including understanding of its tissue-specific roles, finding additional interacting proteins and their relationships. Understanding the basic mechanisms by which SPEG regulates muscle development and function will provide critical insights into these essential processes and help identify therapeutic targets in SPEG-related disorders. Full article

(This article belongs to the Special Issue The Genetic and Molecular Basis of Congenital Myopathies and Various Rare Diseases)

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