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Collagen VI-Related Myopathies—COL6-RMs
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Collagen VI-Related Myopathies—COL6-RMs

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 (28 February 2023) | Viewed by 16169

Special Issue Editors

Prof. Dr. Luciano Merlini

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Guest Editor
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
Interests: Duchenne muscular dystrophy; Ullrich congenital muscular dystrophy; Bethlem myopathy; myosclerosis myopathy; Charcot–Marie–Tooth disease (CMT); clinical trials
Prof. Dr. Paolo Bonaldo

E-Mail Website
Guest Editor
Lab of Matrix Biology and Functional Genomics, Department of Molecular Medicine, University of Padova, Padova, Italy
Interests: collagen VI myopathies
Prof. Dr. Shireen Lamandé

E-Mail Website
Guest Editor
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia
Interests: collagen disorders; extracellular matrix; cartilage; muscle

Special Issue Information

Dear Colleagues,

We are excited to announce a Special Issue of the Journal of International Molecular Sciences that focuses on collagen VI-related myopathies—COL6-RMs.

Collagen VI, encoded by COL6A1–COL6A6 genes, is a component of the extracellular matrix of almost all connective tissues. Mutations in the COL6A1, COL6A2, and COL6A3 genes result in either the absence or malformation of the microfibrils, causing a spectrum of muscle disorders: Bethlem myopathy (BM), Ullrich congenital muscular dystrophy (UCMD), myosclerosis myopathy (MM), and a phenotype of intermediate severity between BM and UCMD.

Key pathomolecular mechanisms involved in these myopathies are related to a defective autophagy with an inability to remove dysfunctional mitochondria that cause persistent opening of the permeability transition pore, a reduction in ATP synthesis, and reactive oxygen species generation.

Proof-of-concept treatments in animal models and in patients have successfully targeted both defective autophagy and mitochondrial dysfunction.  

This Special Issue aims to answer both unresolved questions and explore new territories. The principal potential topics to be covered include (1) how collagen VI matrix defects cause cellular defects, (2) why muscle fibers in COL6-RMs have an earlier peripheral demise, (3) pathological aspects of fascia, skin, subcutaneous tissue, adipose tissue, joints, tendons, ligaments (OPLL), neuromuscular junctions, peripheral nerves and the central nervous system due to collagen VI defects in animal models and in patients, (4) the three minor collagen VI chains  (α4, α5, α6) and their more restricted distribution, (5) new animal models, (6) the effect of different types of gene mutations, (7) peculiar clinical aspects, (8) natural history, (9) respiratory treatment, (10) orthopedic surgery of deformities, and (11) drug and gene therapy. A list of potential topics is provided in the Keywords section below.

Research articles, reviews, and short communications are invited. All papers will undergo peer review.

Prof. Dr. Luciano Merlini
Prof. Dr. Paolo Bonaldo
Prof. Dr. Shireen Lamandé
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. 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

  • collagen type VI
  • COL6A1, COL6A2, COL6A3, COL6A4, COL6A5, COL6A6
  • Ullrich congenital muscular dystrophy
  • Bethlem myopathy
  • myosclerosis myopathy
  • animal models
  • orthopedic surgery of spine and limb deformities
  • drug and gene therapy

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Published Papers (6 papers)

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Research

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20 pages, 3452 KiB  
Article
New Clinical and Immunofluorescence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients
by Luciano Merlini, Patrizia Sabatelli, Francesca Gualandi, Edoardo Redivo, Alberto Di Martino and Cesare Faldini
Int. J. Mol. Sci. 2023, 24(15), 12474; https://doi.org/10.3390/ijms241512474 - 5 Aug 2023
Cited by 6 | Viewed by 1801
Abstract
Pathogenetic mechanism recognition and proof-of-concept clinical trials were performed in our patients affected by collagen VI-related myopathies. This study, which included 69 patients, aimed to identify innovative clinical data to better design future trials. Among the patients, 33 had Bethlem myopathy (BM), 24 [...] Read more.
Pathogenetic mechanism recognition and proof-of-concept clinical trials were performed in our patients affected by collagen VI-related myopathies. This study, which included 69 patients, aimed to identify innovative clinical data to better design future trials. Among the patients, 33 had Bethlem myopathy (BM), 24 had Ullrich congenital muscular dystrophy (UCMD), 7 had an intermediate phenotype (INTM), and five had myosclerosis myopathy (MM). We obtained data on muscle strength, the degree of contracture, immunofluorescence, and genetics. In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion. These findings should be considered when recruiting BM patients for future trials. All the MM patients had axial and limb contractures that limited both the flexion and extension ranges of motion, and a limitation in mouth opening. The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype. However, biopsies from the same patient or from patients with the same mutation taken at different times showed a progressive increase in protein expression with age. The new finding of the time-dependent modulation of collagen VI expression should be considered in genetic correction trials. Full article
(This article belongs to the Special Issue Collagen VI-Related Myopathies—COL6-RMs)
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10 pages, 4204 KiB  
Article
Alopecia in Patients with Collagen VI-Related Myopathies: A Novel/Unrecognized Scalp Phenotype
by Michela Starace, Francesca Pampaloni, Francesca Bruni, Federico Quadrelli, Stephano Cedirian, Carlotta Baraldi, Cosimo Misciali, Alberto Di Martino, Patrizia Sabatelli, Luciano Merlini and Bianca Maria Piraccini
Int. J. Mol. Sci. 2023, 24(7), 6678; https://doi.org/10.3390/ijms24076678 - 3 Apr 2023
Cited by 2 | Viewed by 1787
Abstract
Collagen VI-related myopathies are characterized by severe muscle involvement and skin involvement (keratosis pilaris and impaired healing with the development of abnormal scars, especially keloids). Scalp involvement and hair loss have not been reported among cutaneous changes associated with collagen VI mutations. The [...] Read more.
Collagen VI-related myopathies are characterized by severe muscle involvement and skin involvement (keratosis pilaris and impaired healing with the development of abnormal scars, especially keloids). Scalp involvement and hair loss have not been reported among cutaneous changes associated with collagen VI mutations. The aim of this study is to describe the clinical, trichoscopic, and histological findings of the scalp changes in patients affected by COL VI mutations and to estimate their prevalence. Patients with Ullrich congenital muscular dystrophy were enrolled and underwent clinical and trichoscopic examinations and a scalp biopsy for histopathology. Five patients were enrolled, and all complained of hair loss and scalp itching. One patient showed yellow interfollicular scales with erythema and dilated, branched vessels, and the histological findings were suggestive of scalp psoriasis. Two patients presented with scarring alopecia patches on the vertex area, and they were histologically diagnosed with folliculitis decalvans. The last two patients presented with scaling and hair thinning, but they were both diagnosed with folliculitis and perifolliculitis. Ten more patients answered to a “scalp involvement questionnaire”, and six of them confirmed to have or have had scalp disorders and/or itching. Scalp involvement can be associated with COL VI mutations and should be investigated. Full article
(This article belongs to the Special Issue Collagen VI-Related Myopathies—COL6-RMs)
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14 pages, 11764 KiB  
Article
Extracellular Matrix Disorganization and Sarcolemmal Alterations in COL6-Related Myopathy Patients with New Variants of COL6 Genes
by Simona Zanotti, Francesca Magri, Sabrina Salani, Laura Napoli, Michela Ripolone, Dario Ronchi, Francesco Fortunato, Patrizia Ciscato, Daniele Velardo, Maria Grazia D’Angelo, Francesca Gualandi, Vincenzo Nigro, Monica Sciacco, Stefania Corti, Giacomo Pietro Comi and Daniela Piga
Int. J. Mol. Sci. 2023, 24(6), 5551; https://doi.org/10.3390/ijms24065551 - 14 Mar 2023
Cited by 4 | Viewed by 2005
Abstract
Collagen VI is a heterotrimeric protein expressed in several tissues and involved in the maintenance of cell integrity. It localizes at the cell surface, creating a microfilamentous network that links the cytoskeleton to the extracellular matrix. The heterotrimer consists of three chains encoded [...] Read more.
Collagen VI is a heterotrimeric protein expressed in several tissues and involved in the maintenance of cell integrity. It localizes at the cell surface, creating a microfilamentous network that links the cytoskeleton to the extracellular matrix. The heterotrimer consists of three chains encoded by COL6A1, COL6A2 and COL6A3 genes. Recessive and dominant molecular defects cause two main disorders, the severe Ullrich congenital muscular dystrophy and the relatively mild and slowly progressive Bethlem myopathy. We analyzed the clinical aspects, pathological features and mutational spectrum of 15 COL6-mutated patients belonging to our cohort of muscular dystrophy probands. Patients presented a heterogeneous phenotype ranging from severe forms to mild adult-onset presentations. Molecular analysis by NGS detected 14 different pathogenic variants, three of them so far unreported. Two changes, localized in the triple-helical domain of COL6A1, were associated with a more severe phenotype. Histological, immunological and ultrastructural techniques were employed for the validation of the genetic variants; they documented the high variability in COL6 distribution and the extracellular matrix disorganization, highlighting the clinical heterogeneity of our cohort. The combined use of these different technologies is pivotal in the diagnosis of COL6 patients. Full article
(This article belongs to the Special Issue Collagen VI-Related Myopathies—COL6-RMs)
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12 pages, 1503 KiB  
Article
A Schematic Approach to Defining the Prevalence of COL VI Variants in Five Years of Next-Generation Sequencing
by Gemma Marinella, Guja Astrea, Bianca Buchignani, Denise Cassandrini, Stefano Doccini, Massimiliano Filosto, Daniele Galatolo, Salvatore Gallone, Fabio Giannini, Diego Lopergolo, Maria Antonietta Maioli, Francesca Magri, Alessandro Malandrini, Paola Mandich, Francesco Mari, Roberto Massa, Sabrina Mata, Federico Melani, Maurizio Moggio, Tiziana E. Mongini, Rosa Pasquariello, Elena Pegoraro, Federica Ricci, Giulia Ricci, Carmelo Rodolico, Anna Rubegni, Gabriele Siciliano, Martina Sperti, Chiara Ticci, Paola Tonin, Filippo M. Santorelli and Roberta Battiniadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(23), 14567; https://doi.org/10.3390/ijms232314567 - 23 Nov 2022
Cited by 5 | Viewed by 1913
Abstract
Objective: To define the prevalence of variants in collagen VI genes through a next-generation sequencing (NGS) approach in undiagnosed patients with suspected neuromuscular disease and to propose a diagnostic flowchart to assess the real pathogenicity of those variants. Methods: In the past five [...] Read more.
Objective: To define the prevalence of variants in collagen VI genes through a next-generation sequencing (NGS) approach in undiagnosed patients with suspected neuromuscular disease and to propose a diagnostic flowchart to assess the real pathogenicity of those variants. Methods: In the past five years, we have collected clinical and molecular information on 512 patients with neuromuscular symptoms referred to our center. To pinpoint variants in COLVI genes and corroborate their real pathogenicity, we sketched a multistep flowchart, taking into consideration the bioinformatic weight of the gene variants, their correlation with clinical manifestations and possible effects on protein stability and expression. Results: In Step I, we identified variants in COLVI-related genes in 48 patients, of which three were homozygous variants (Group 1). Then, we sorted variants according to their CADD score, clinical data and complementary studies (such as muscle and skin biopsy, study of expression of COLVI on fibroblast or muscle and muscle magnetic resonance). We finally assessed how potentially pathogenic variants (two biallelic and 12 monoallelic) destabilize COL6A1-A2-A3 subunits. Overall, 15 out of 512 patients were prioritized according to this pipeline. In seven of them, we confirmed reduced or absent immunocytochemical expression of collagen VI in cultured skin fibroblasts or in muscle tissue. Conclusions: In a real-world diagnostic scenario applied to heterogeneous neuromuscular conditions, a multistep integration of clinical and molecular data allowed the identification of about 3% of those patients harboring pathogenetic collagen VI variants. Full article
(This article belongs to the Special Issue Collagen VI-Related Myopathies—COL6-RMs)
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12 pages, 5662 KiB  
Article
The Role of Type VI Collagen in Alveolar Bone
by Taishi Komori, Hai Pham, Priyam Jani, Sienna Perry, Yan Wang, Tina M. Kilts, Li Li and Marian F. Young
Int. J. Mol. Sci. 2022, 23(22), 14347; https://doi.org/10.3390/ijms232214347 - 18 Nov 2022
Cited by 6 | Viewed by 2142
Abstract
Many studies have been conducted to elucidate the role of Type VI collagen in muscle and tendon, however, its role in oral tissues remains unclear. In this study, an α2(VI) deficient mouse (Col6α2-KO) model was used to examine the role of [...] Read more.
Many studies have been conducted to elucidate the role of Type VI collagen in muscle and tendon, however, its role in oral tissues remains unclear. In this study, an α2(VI) deficient mouse (Col6α2-KO) model was used to examine the role of Type VI collagen in oral tissues. Tissue volume and mineral density were measured in oral tissues by µCT. Proteome analysis was performed using protein extracted from alveolar bone. In addition, alveolar bone was evaluated with a periodontitis induced model. µCT analysis showed the Col6α2-KO mice had less volume of alveolar bone, dentin and dental pulp, while the width of periodontal ligament (PDL) was greater than WT. The mineral density in alveolar bone and dentin were elevated in Col6α2-KO mice compared with WT. Our proteome analysis showed significant changes in proteins related to ECM organization and elevation of proteins associated with biomineralization in the Col6α2-KO mice. In induced periodontitis, Col6α2-KO mice had greater alveolar bone loss compared with WT. In conclusion, Type VI collagen has a role in controlling biomineralization in alveolar bone and that changes in the ECM of alveolar bone could be associated with greater bone loss due to periodontitis. Full article
(This article belongs to the Special Issue Collagen VI-Related Myopathies—COL6-RMs)
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Review

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22 pages, 1480 KiB  
Review
Collagen VI in the Musculoskeletal System
by Alberto Di Martino, Matilde Cescon, Claudio D’Agostino, Francesco Schilardi, Patrizia Sabatelli, Luciano Merlini and Cesare Faldini
Int. J. Mol. Sci. 2023, 24(6), 5095; https://doi.org/10.3390/ijms24065095 - 7 Mar 2023
Cited by 24 | Viewed by 4880
Abstract
Collagen VI exerts several functions in the tissues in which it is expressed, including mechanical roles, cytoprotective functions with the inhibition of apoptosis and oxidative damage, and the promotion of tumor growth and progression by the regulation of cell differentiation and autophagic mechanisms. [...] Read more.
Collagen VI exerts several functions in the tissues in which it is expressed, including mechanical roles, cytoprotective functions with the inhibition of apoptosis and oxidative damage, and the promotion of tumor growth and progression by the regulation of cell differentiation and autophagic mechanisms. Mutations in the genes encoding collagen VI main chains, COL6A1, COL6A2 and COL6A3, are responsible for a spectrum of congenital muscular disorders, namely Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy (MM), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. No effective therapeutic strategy is available so far for these diseases; moreover, the effects of collagen VI mutations on other tissues is poorly investigated. The aim of this review is to outline the role of collagen VI in the musculoskeletal system and to give an update about the tissue-specific functions revealed by studies on animal models and from patients’ derived samples in order to fill the knowledge gap between scientists and the clinicians who daily manage patients affected by collagen VI-related myopathies. Full article
(This article belongs to the Special Issue Collagen VI-Related Myopathies—COL6-RMs)
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