Research

12 pages, 927 KiB

Open AccessCommunication

Serum-Circulating microRNAs in Sporadic Inclusion Body Myositis

by Matteo Lucchini, Valeria De Arcangelis, Massimo Santoro, Roberta Morosetti, Aldobrando Broccolini and Massimiliano Mirabella

Int. J. Mol. Sci. 2023, 24(13), 11139; https://doi.org/10.3390/ijms241311139 - 06 Jul 2023

Cited by 1 | Viewed by 919

Abstract

Background: Sporadic inclusion body myositis (s-IBM) represents a unique disease within idiopathic inflammatory myopathies with a dual myodegenerative–autoimmune physiopathology and a lack of an efficacious treatment. Circulating miRNA expression could expand our knowledge of s-IBM patho-mechanisms and provide new potential disease biomarkers. To [...] Read more.

Background: Sporadic inclusion body myositis (s-IBM) represents a unique disease within idiopathic inflammatory myopathies with a dual myodegenerative–autoimmune physiopathology and a lack of an efficacious treatment. Circulating miRNA expression could expand our knowledge of s-IBM patho-mechanisms and provide new potential disease biomarkers. To evaluate the expression of selected pre-amplified miRNAs in the serum of s-IBM patients compared to those of a sex- and age-matched healthy control group, we enrolled 14 consecutive s-IBM patients and 8 sex- and age-matched healthy controls. By using two different normalization approaches, we found one downregulated and three upregulated miRNAs. hsa-miR-192-5p was significantly downregulated, while hsa-miR-372-3p was found to be upregulated more in the s-IBM patients compared to the level of the controls. The other two miRNAs had a very low expression levels (raw Ct data > 29). hsa-miR-192-5p and hsa-miR-372-3p were found to be significantly dysregulated in the serum of s-IBM patients. These miRNAs are involved in differentiation and regeneration processes, thus possibly reflecting pathological mechanisms in s-IBM muscles and potentially representing disease biomarkers. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 2.0)

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15 pages, 1877 KiB

Open AccessArticle

Dystrophin (DMD) Missense Variant in Cats with Becker-Type Muscular Dystrophy

by Stephanie Hilton, Matthias Christen, Thomas Bilzer, Vidhya Jagannathan, Tosso Leeb and Urs Giger

Int. J. Mol. Sci. 2023, 24(4), 3192; https://doi.org/10.3390/ijms24043192 - 06 Feb 2023

Cited by 3 | Viewed by 3750

Abstract

Muscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few DMD gene variants have been identified in animals. Here, we characterize [...] Read more.

Muscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few DMD gene variants have been identified in animals. Here, we characterize the clinical, histopathological, and molecular genetic aspects of a family of Maine Coon crossbred cats with clinically mild and slowly progressive muscular dystrophy. Two young adult male littermate cats exhibited abnormal gait and muscular hypertrophy with macroglossia. Serum creatine kinase activities were highly increased. Histopathologically, dystrophic skeletal muscle exhibited marked structural changes including atrophic, hypertrophic, and necrotic muscle fibers. Immunohistochemistry showed irregularly reduced expression of dystrophin but the staining of other muscle proteins such as β- and γ-sarcoglycans as well as desmin was also diminished. Whole genome sequencing of one affected cat and genotyping of the littermate found both to be hemizygous mutant at a single DMD missense variant (c.4186C>T). No other protein-changing variants in candidate genes for muscular dystrophy were detected. In addition, one clinically healthy male littermate was hemizygous wildtype, while the queen and one female littermate were clinically healthy, but heterozygous. The predicted amino acid exchange (p.His1396Tyr) resides in a conserved central rod spectrin domain of dystrophin. Various protein modeling programs did not predict major disruption of the dystrophin protein by this substitution, but the altered charge of the region may still affect protein function. This study represents the first genotype-to-phenotype correlation of Becker-type dystrophin deficiency in companion animals. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 2.0)

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11 pages, 978 KiB

Open AccessArticle

A Greek National Cross-Sectional Study on Myotonic Dystrophies

by Georgios K. Papadimas, Constantinos Papadopoulos, Kyriaki Kekou, Chrisoula Kartanou, Athina Kladi, Evangelia Nitsa, Christalena Sofocleous, Evangelia Tsanou, Ioannis Sarmas, Stefania Kaninia, Elisabeth Chroni, Georgios Tsivgoulis, Vasilios Kimiskidis, Marianthi Arnaoutoglou, Leonidas Stefanis, Marios Panas, Georgios Koutsis, Georgia Karadima and Joanne Traeger-Synodinos

Int. J. Mol. Sci. 2022, 23(24), 15507; https://doi.org/10.3390/ijms232415507 - 07 Dec 2022

Cited by 3 | Viewed by 1438

Abstract

Myotonic Dystrophies (DM, Dystrophia Myotonia) are autosomal dominant inherited myopathies with a high prevalence across different ethnic regions. Despite some differences, mainly due to the pattern of muscle involvement and the age of onset, both forms, DM1 and DM2, share many clinical and [...] Read more.

Myotonic Dystrophies (DM, Dystrophia Myotonia) are autosomal dominant inherited myopathies with a high prevalence across different ethnic regions. Despite some differences, mainly due to the pattern of muscle involvement and the age of onset, both forms, DM1 and DM2, share many clinical and genetic similarities. In this study, we retrospectively analyzed the medical record files of 561 Greek patients, 434 with DM1 and 127 with DM2 diagnosed in two large academic centers between 1994–2020. The mean age at onset of symptoms was 26.2 ± 15.3 years in DM1 versus 44.4 ± 17.0 years in DM2 patients, while the delay of diagnosis was 10 and 7 years for DM1 and DM2 patients, respectively. Muscle weakness was the first symptom in both types, while myotonia was more frequent in DM1 patients. Multisystemic involvement was detected in the great majority of patients, with cataracts being one of the most common extramuscular manifestations, even in the early stages of disease expression. In conclusion, the present work, despite some limitations arising from the retrospective collection of data, is the first record of a large number of Greek patients with myotonic dystrophy and emphasizes the need for specialized neuromuscular centers that can provide genetic counseling and a multidisciplinary approach. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 2.0)

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12 pages, 965 KiB

Open AccessArticle

Objective Evaluation of Clinical Actionability for Genes Involved in Myopathies: 63 Genes with a Medical Value for Patient Care

by Maude Vecten, Emmanuelle Pion, Marc Bartoli, Raul Juntas Morales, Damien Sternberg, John Rendu, Tanya Stojkovic, Cécile Acquaviva Bourdain, Corinne Métay, Isabelle Richard, Mathieu Cerino, Mathieu Milh, Emmanuelle Campana-Salort, Svetlana Gorokhova, Nicolas Levy, Xénia Latypova, Gisèle Bonne, Valérie Biancalana, François Petit, Annamaria Molon, Aurélien Perrin, Pascal Laforêt, Shahram Attarian, Martin Krahn and Mireille Cossée Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(15), 8506; https://doi.org/10.3390/ijms23158506 - 31 Jul 2022

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Abstract

The implementation of high-throughput diagnostic sequencing has led to the generation of large amounts of mutational data, making their interpretation more complex and responsible for long delays. It has been important to prioritize certain analyses, particularly those of “actionable” genes in diagnostic situations, [...] Read more.

The implementation of high-throughput diagnostic sequencing has led to the generation of large amounts of mutational data, making their interpretation more complex and responsible for long delays. It has been important to prioritize certain analyses, particularly those of “actionable” genes in diagnostic situations, involving specific treatment and/or management. In our project, we carried out an objective assessment of the clinical actionability of genes involved in myopathies, for which only few data obtained methodologically exist to date. Using the ClinGen Actionability criteria, we scored the clinical actionability of all 199 genes implicated in myopathies published by FILNEMUS for the “National French consensus on gene Lists for the diagnosis of myopathies using next generation sequencing”. We objectified that 63 myopathy genes were actionable with the currently available data. Among the 36 myopathy genes with the highest actionability scores, only 8 had been scored to date by ClinGen. The data obtained through these methodological tools are an important resource for strategic choices in diagnostic approaches and the management of genetic myopathies. The clinical actionability of genes has to be considered as an evolving concept, in relation to progresses in disease knowledge and therapeutic approaches. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 2.0)

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13 pages, 6777 KiB

Open AccessArticle

Compound Heterozygous FKTN Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant α-Dystroglycan Pattern

by Anna Gaertner, Lidia Burr, Baerbel Klauke, Andreas Brodehl, Kai Thorsten Laser, Karin Klingel, Jens Tiesmeier, Uwe Schulz, Edzard zu Knyphausen, Jan Gummert and Hendrik Milting

Int. J. Mol. Sci. 2022, 23(12), 6685; https://doi.org/10.3390/ijms23126685 - 15 Jun 2022

Cited by 3 | Viewed by 1544

Abstract

Fukutin encoded by FKTN is a ribitol 5-phosphate transferase involved in glycosylation of α-dystroglycan. It is known that mutations in FKTN affect the glycosylation of α-dystroglycan, leading to a dystroglycanopathy. Dystroglycanopathies are a group of syndromes with a broad clinical spectrum including dilated [...] Read more.

Fukutin encoded by FKTN is a ribitol 5-phosphate transferase involved in glycosylation of α-dystroglycan. It is known that mutations in FKTN affect the glycosylation of α-dystroglycan, leading to a dystroglycanopathy. Dystroglycanopathies are a group of syndromes with a broad clinical spectrum including dilated cardiomyopathy and muscular dystrophy. In this study, we reported the case of a patient with muscular dystrophy, early onset dilated cardiomyopathy, and elevated creatine kinase levels who was a carrier of the compound heterozygous variants p.Ser299Arg and p.Asn442Ser in FKTN. Our work showed that compound heterozygous mutations in FKTN lead to a loss of fully glycosylated α-dystroglycan and result in cardiomyopathy and end-stage heart failure at a young age. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 2.0)

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Review

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12 pages, 272 KiB

Open AccessReview

Remarks on Mitochondrial Myopathies

by Patrizia Bottoni, Giulia Gionta and Roberto Scatena

Int. J. Mol. Sci. 2023, 24(1), 124; https://doi.org/10.3390/ijms24010124 - 21 Dec 2022

Cited by 5 | Viewed by 1767

Abstract

Mitochondrial myopathies represent a heterogeneous group of diseases caused mainly by genetic mutations to proteins that are related to mitochondrial oxidative metabolism. Meanwhile, a similar etiopathogenetic mechanism (i.e., a deranged oxidative phosphorylation and a dramatic reduction of ATP synthesis) reveals that the evolution [...] Read more.

Mitochondrial myopathies represent a heterogeneous group of diseases caused mainly by genetic mutations to proteins that are related to mitochondrial oxidative metabolism. Meanwhile, a similar etiopathogenetic mechanism (i.e., a deranged oxidative phosphorylation and a dramatic reduction of ATP synthesis) reveals that the evolution of these myopathies show significant differences. However, some physiological and pathophysiological aspects of mitochondria often reveal other potential molecular mechanisms that could have a significant pathogenetic role in the clinical evolution of these disorders, such as: i. a deranged ROS production both in term of signaling and in terms of damaging molecules; ii. the severe modifications of nicotinamide adenine dinucleotide (NAD)+/NADH, pyruvate/lactate, and α-ketoglutarate (α-KG)/2- hydroxyglutarate (2-HG) ratios. A better definition of the molecular mechanisms at the basis of their pathogenesis could improve not only the clinical approach in terms of diagnosis, prognosis, and therapy of these myopathies but also deepen the knowledge of mitochondrial medicine in general. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 2.0)

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10 pages, 1499 KiB

Open AccessCase Report

Bi-Allelic DES Gene Variants Causing Autosomal Recessive Myofibrillar Myopathies Affecting Both Skeletal Muscles and Cardiac Function

by Maria Elena Onore, Marco Savarese, Esther Picillo, Luigia Passamano, Vincenzo Nigro and Luisa Politano

Int. J. Mol. Sci. 2022, 23(24), 15906; https://doi.org/10.3390/ijms232415906 - 14 Dec 2022

Cited by 3 | Viewed by 1583

Abstract

Mutations in the human desmin gene (DES) may cause both autosomal dominant and recessive cardiomyopathies leading to heart failure, arrhythmias and atrio-ventricular blocks, or progressive myopathies. Cardiac conduction disorders, arrhythmias and cardiomyopathies usually associated with progressive myopathy are the main manifestations of [...] Read more.

Mutations in the human desmin gene (DES) may cause both autosomal dominant and recessive cardiomyopathies leading to heart failure, arrhythmias and atrio-ventricular blocks, or progressive myopathies. Cardiac conduction disorders, arrhythmias and cardiomyopathies usually associated with progressive myopathy are the main manifestations of autosomal dominant desminopathies, due to mono-allelic pathogenic variants. The recessive forms, due to bi-allelic variants, are very rare and exhibit variable phenotypes in which premature sudden cardiac death could also occur in the first or second decade of life. We describe a further case of autosomal recessive desminopathy in an Italian boy born of consanguineous parents, who developed progressive myopathy at age 12, and dilated cardiomyopathy four years later and died of intractable heart failure at age 17. Next Generation Sequencing (NGS) analysis identified the homozygous loss-of-function variant c.634C>T; p.Arg212*, which was likely inherited from both parents. Furthermore, we performed a comparison of clinical and genetic results observed in our patient with those of cases so far reported in the literature. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 2.0)

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6 pages, 398 KiB

Open AccessPerspective

Golgi Complex form and Function: A Potential Hub Role Also in Skeletal Muscle Pathologies?

by Luana Toniolo, Giuseppe Sirago, Nicola Fiotti and Emiliana Giacomello

Int. J. Mol. Sci. 2022, 23(23), 14989; https://doi.org/10.3390/ijms232314989 - 30 Nov 2022

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Abstract

A growing number of disorders has been associated with mutations in the components of the vesicular transport machinery. The early secretory pathway consists of Endoplasmic Reticulum, numerous vesicles, and the Golgi Complex (GC), which work together to modify and package proteins to deliver [...] Read more.

A growing number of disorders has been associated with mutations in the components of the vesicular transport machinery. The early secretory pathway consists of Endoplasmic Reticulum, numerous vesicles, and the Golgi Complex (GC), which work together to modify and package proteins to deliver them to their destination. The GC is a hub organelle, crucial for organization of the other secretory pathway components. As a consequence, GC’s form and function are key players in the pathogenesis of several disorders. Skeletal muscle (SKM) damage can be caused by defective protein modifications and traffic, as observed in some Limb girdle muscular dystrophies. Interestingly, in turn, muscle damage in Duchenne dystrophic SKM cells also includes the alteration of GC morphology. Based on the correlation between GC’s form and function described in non-muscle diseases, we suggest a key role for this hub organelle also in the onset and progression of some SKM disorders. An altered GC could affect the secretory pathway via primary (e.g., mutation of a glycosylation enzyme), or secondary mechanisms (e.g., GC mis-localization in Duchenne muscles), which converge in SKM cell failure. This evidence induces considering the secretory pathway as a potential therapeutic target in the treatment of muscular dystrophies. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 2.0)

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8 pages, 640 KiB

Open AccessCase Report

Turner Syndrome Mosaicism 45,X/46,XY with Genital Ambiguity and Duchenne Muscular Dystrophy: Translational Approach of a Rare Italian Case

by Bruno Lamanna, Marina Vinciguerra, Miriam Dellino, Gabriele Cascella, Gerardo Cazzato, Enrica Macorano, Antonio Malvasi, Salvatore Scacco, Ettore Cicinelli, Vera Loizzi, Antonella Vimercati, Gennaro Cormio, Francesco Paduano, Eliano Cascardi and Marco Tatullo

Int. J. Mol. Sci. 2022, 23(22), 14408; https://doi.org/10.3390/ijms232214408 - 19 Nov 2022

Cited by 1 | Viewed by 5954

Abstract

Turner syndrome (gonadal dysgenesis with short stature and sterility) is characterized by chromosomal karyotype 45,X in 50% of cases or by mosaicism (45,X/46,XX and 45,X/46,XY) in 30–40% or X structural defects (deletions, long arm isochromosome, ring chromosome). When mosaic Turner syndrome (TS) occurs [...] Read more.

Turner syndrome (gonadal dysgenesis with short stature and sterility) is characterized by chromosomal karyotype 45,X in 50% of cases or by mosaicism (45,X/46,XX and 45,X/46,XY) in 30–40% or X structural defects (deletions, long arm isochromosome, ring chromosome). When mosaic Turner syndrome (TS) occurs with a Y chromosome, there may be ambiguous genitalia. Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disease with an X-Linked recessive pattern of inheritance that predominantly affects males, while females are usually asymptomatic. DMD has also been observed in groups of females affected by TS, not homozygous for the mutation. Here, we report a case of an Indian neonate born with ambiguous genitalia diagnosed prenatally by ultrasound who had a karyotype of 45,X/46,XY and who also had Duchenne muscular dystrophy caused by a de novo mutation in the DMD gene. Physical examination was normal without the typical dysmorphic features of TS with the exception of the genitourinary system showing ambiguous genitalia. Gender was assigned as female. At the age of three years, she had increasing difficulty walking, running, jumping and climbing stairs, proximal upper and lower extremity muscle weakness and a positive Gowers’ sign. In addition, the serum creatine kinase (CK) value was over 30X the upper limit of normal. This study shows that DMD can occur in females with TS having 45,X/46,XY mosaicism and that this coexistence should be considered in women affected by TS who start to develop potential typical symptoms such as motor or developmental delay. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 2.0)

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8 pages, 1387 KiB

Open AccessCase Report

Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy

by Luca Bosco, Daniela Leone, Laura Costa Comellas, Mauro Monforte, Marika Pane, Eugenio Mercuri, Enrico Bertini, Adele D’Amico and Fabiana Fattori

Int. J. Mol. Sci. 2022, 23(18), 10274; https://doi.org/10.3390/ijms231810274 - 07 Sep 2022

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Abstract

X-linked myotubular myopathy (XLMTM) is a severe form of centronuclear myopathy, characterized by generalized weakness and respiratory insufficiency, associated with pathogenic variants in the MTM1 gene. NGS targeted sequencing on the DNA of a three-month-old child affected by XLMTM identified the novel hemizygous [...] Read more.

X-linked myotubular myopathy (XLMTM) is a severe form of centronuclear myopathy, characterized by generalized weakness and respiratory insufficiency, associated with pathogenic variants in the MTM1 gene. NGS targeted sequencing on the DNA of a three-month-old child affected by XLMTM identified the novel hemizygous MTM1 c.1261-5T>G intronic variant, which interferes with the normal splicing process, generating two different abnormal transcripts simultaneously expressed in the patient’s muscular cells. The first aberrant transcript, induced by the activation of a cryptic splice site in intron 11, includes four intronic nucleotides upstream of exon 12, resulting in a shift in the transcript reading frame and introducing a new premature stop codon in the catalytic domain of the protein (p.Arg421SerfsTer7). The second aberrant MTM1 transcript, due to the lack of recognition of the 3′ acceptor splice site of intron 11 from the spliceosome complex, leads to the complete skipping of exon 12. We expanded the genotypic spectrum of XLMTM underlying the importance of intron–exons boundaries sequencing in male patients affected by XLMTM. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 2.0)

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