Landscape Analysis of COL6A1, COL6A2, and COL6A3 Pathogenic Variants in a Large Italian Cohort Presenting with Collagen VI-Related Myopathies: A Nationwide Report

Collagen VI is an extracellular matrix component encoded by <i>COL6A1</i>, <i>COL6A2</i> and <i>COL6A3</i> genes. Causative variants in these genes are associated with the following collagen VI-related myopathies: severe Ullrich congenital muscular dystrophy (UCMD), milder Bethlem myopathy (BM) and intermediate phenotypes (INT). We report the mutation landscape of <i>COL6A</i> genes in 138 Italian patients affected with a collagen VI-related phenotype. The patient cohort included 44 (32%) UCMD, 9 (7%) INT, 61 (44%) BM and 21 (15%) INT/BM patients; 3 patients (2%) with a myosclerosis myopathy (MM) phenotype were also considered. We identified 104 different variants: 26 in <i>COL6A1</i> (25%), 52 in <i>COL6A2</i> (50%) and 26 in <i>COL6A3</i> (25%). The variant spectrum includes missense, splicing, small indel, frameshifting and nonsense variants. Glycine substitutions in the triple helical domain of the collagen VI protein are the commonest variants and occur in all phenotypes. Our genetic profiling disclosed a unique mutation scenario and phenotypic association of the <i>COL6A2</i> gene with respect to <i>COL6A1</i> and <i>COL6A3</i>, which may be related to a different evolutive history. Landscape mutation analysis of variants occurring in ultrarare conditions, such as collagen VI-related myopathies, is crucial to better understand the variations' profile and to gain insight into fundamental knowledge about gene structure and its evolutive origin.

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Journal
Biomolecules
Published
2025-10-08
DOI
https://doi.org/10.3390/biom15101426
Primary Topic
Cell Adhesion Molecules Research
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article
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article

Landscape Analysis of COL6A1, COL6A2, and COL6A3 Pathogenic Variants in a Large Italian Cohort Presenting with Collagen VI-Related Myopathies: A Nationwide Report

Elena Pegoraro, Rita Selvatici, Adele D’Amico, Roberto Massa et al.
Biomolecules
Cell Adhesion Molecules Research
article

Landscape Analysis of COL6A1, COL6A2, and COL6A3 Pathogenic Variants in a Large Italian Cohort Presenting with Collagen VI-Related Myopathies: A Nationwide Report

Elena Pegoraro, Rita Selvatici, Adele D’Amico, Roberto Massa, Paolo Gasparini, Sara Gibertini, Francesca Massaro, F. Fortunato, Alice Margutti, Tiziana Mongini, Massimiliano Filosto, Federica Ricci, Luciano Merlini, Marianna Scutifero, Carlo Fusco, Sonia Messina, Francesca Gualandi, Eugenio Maria Mercuri, Alessandra Ferlini, Monica Traverso, Marika Pane, Antonella Pini, Marcella Neri, Enrico Bertini, Carmelo Rodolico, Marina Pedemonte, Chiara Fiorillo, Angela Lucia Berardinelli, Isabella Moroni, Lorenzo Maggi, Fabiana Vercellino, Luisa Politano, Enzo Ricci, Giulia Greco, Claudio Bruno, Esther Picillo, Laura Fiocco
article en

Abstract

Collagen VI is an extracellular matrix component encoded by <i>COL6A1</i>, <i>COL6A2</i> and <i>COL6A3</i> genes. Causative variants in these genes are associated with the following collagen VI-related myopathies: severe Ullrich congenital muscular dystrophy (UCMD), milder Bethlem myopathy (BM) and intermediate phenotypes (INT). We report the mutation landscape of <i>COL6A</i> genes in 138 Italian patients affected with a collagen VI-related phenotype. The patient cohort included 44 (32%) UCMD, 9 (7%) INT, 61 (44%) BM and 21 (15%) INT/BM patients; 3 patients (2%) with a myosclerosis myopathy (MM) phenotype were also considered. We identified 104 different variants: 26 in <i>COL6A1</i> (25%), 52 in <i>COL6A2</i> (50%) and 26 in <i>COL6A3</i> (25%). The variant spectrum includes missense, splicing, small indel, frameshifting and nonsense variants. Glycine substitutions in the triple helical domain of the collagen VI protein are the commonest variants and occur in all phenotypes. Our genetic profiling disclosed a unique mutation scenario and phenotypic association of the <i>COL6A2</i> gene with respect to <i>COL6A1</i> and <i>COL6A3</i>, which may be related to a different evolutive history. Landscape mutation analysis of variants occurring in ultrarare conditions, such as collagen VI-related myopathies, is crucial to better understand the variations' profile and to gain insight into fundamental knowledge about gene structure and its evolutive origin.

BiomoleculesVol. 15(10)
University of Messina (IT), University of Rome Tor Vergata (IT), University of Padua (IT), University of Trieste (IT), University of Milan (IT), University of Campania "Luigi Vanvitelli" (IT), University of Ferrara (IT), IRCCS Materno Infantile Burlo Garofolo (IT), Istituto Giannina Gaslini (IT), Agostino Gemelli University Polyclinic (IT), Santa Maria Nuova Hospital (IT), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Centro Clinico Nemo (IT), Neuroscience Institute (IT), Institute of Neurological Sciences (IT), Presidio Ospedaliero (IT), Bambino Gesù Children's Hospital (IT), University of Campania "Luigi Vanvitelli" (IT), Ospedale dei Bambini Vittore Buzzi (IT), University of the Sacred Heart (JP), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Ospedale di Prato Santo Stefano (IT), Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo (IT), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Hospital of Prato (IT), University of Turin (IT), University of Brescia (IT), University of Genoa (IT), University of Bologna (IT)
Openalex Percentile: Top 64%
Cell Adhesion Molecules Research
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