Characterization of severe COL6-related dystrophy due to the recurrent variant <i>COL6A1</i> c.930+189C&amp;gt;T

Collagen VI-related dystrophies manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterized by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognized later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of collagen VI-related dystrophy, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA sequencing and whole-genome sequencing, we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterized an international cohort of 44 patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterized by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.

Authors

Institutions

Publication Details

Journal
Brain
Published
2025-04-02
DOI
https://doi.org/10.1093/brain/awaf116
Citations
1
Primary Topic
Muscle Physiology and Disorders
Type
article
Field-Weighted Citation Impact
0.81
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Characterization of severe COL6-related dystrophy due to the recurrent variant COL6A1 c.930+189C&gt;T

Steve D. Wilton, Daniel G. MacArthur, Gita Tauriņa, Gina Norato et al.
1 citations
Brain
Muscle Physiology and Disorders
0.81
article

Characterization of severe COL6-related dystrophy due to the recurrent variant COL6A1 c.930+189C&gt;T

Steve D. Wilton, Daniel G. MacArthur, Gita Tauriņa, Gina Norato, Riley M. McCarty, C. Jimenez‐Mallebrera, James J. Collins, Sara Aguti, Baiba Lāce, Edward Leung, Janbernd Kirschner, M. L. Chu, Raimund Wagener, Monique M. Ryan, Fady Guirguis, Mena T. Scavina, Carla Grosmann, Tanya Stojkovic, Denise McDonald, Beryl B. Cummings, Monkol Lek, Shireen R. Lamandé, Pinki Munot, Susana Quijano‐Roy, Luciano Merlini, Sarah Neuhaus, H.S. Chan, Sandra C. Donkervoort, Giacomo P. Comi, Valérie Allamand, Vikram Bhise, Véronique Bolduc, Francesca Gualandi, Corine Gartioux, Alessandra Ferlini, Adel Shalata, Apurva Sarathy, Grace Yoon, Anna Sárközy, Johanna Palmio, Enrico Bertini, Carsten G. Bönnemann, Rotem Orbach, A. Nascimento, Manu Jokela, Herimela Solomon-Degefa, Russell J. Butterfield, Brian D. Kossak, Payam Mohassel, M. Leach, Ichizo Nishino, Göknur Haliloğlu, Erika Finanger, Sídney M. Gospe, Haiyan Zhou, Daniel Natera‐de Benito, A. Reghan Foley, Alvise Schiavinato, Yoram Nevo, Cristina Jou, M. Troncoso, Carolin D. Freiburg, Ben Cocanougher, Francesco Muntoni, Dimah Saade, Randal Richardson, Cuixia Tian, Ying Hu, Mordechai Shohat
article en
1 citations

Abstract

Collagen VI-related dystrophies manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterized by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognized later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of collagen VI-related dystrophy, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA sequencing and whole-genome sequencing, we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterized an international cohort of 44 patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterized by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.

BrainVol. 148(9)
Rutgers, The State University of New Jersey (US), Broad Institute (US), Cincinnati Children's Hospital Medical Center (US), Dartmouth–Hitchcock Medical Center (US), Hospital Sant Joan de Déu Barcelona (ES), Children’s Institute (US), Royal Children's Hospital (AU), Alfred I. duPont Hospital for Children (US), Inserm (FR), University of Turku (FI), University of Freiburg (DE), Oregon Health & Science University (US), The University of Melbourne (AU), Duke University (US), Technion – Israel Institute of Technology (IL), The University of Western Australia (AU), University of Cologne (DE), University of Toronto (CA), Université de Versailles Saint-Quentin-en-Yvelines (FR), University of Washington (US), University of Utah (US), Sheba Medical Center (IL), Great Ormond Street Hospital (GB), University Medical Center Freiburg (DE), Hospital for Sick Children (CA), Community Health Systems - Dupont Hospital (US), Instituto de Salud Carlos III (ES), Turku University Hospital (FI), Johnson University (US), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Children's Health Ireland at Crumlin (IE), University of California San Diego (US), Sorbonne Université (FR), Rady Children's Hospital-San Diego (US), Assistance Publique – Hôpitaux de Paris (FR), Riga East University Hospital (LV), Gillette Children's Specialty Healthcare (US), National Center of Neurology and Psychiatry (JP), Nemours Children's Health System (US), Schneider Children's Medical Center (IL), National Institute of Neurological Disorders and Stroke (US), Centre for Biomedical Network Research on Rare Diseases (ES), Bnai Zion Medical Center (IL), Institut de Myologie (FR), Children's Clinical University Hospital (LV), Bambino Gesù Children's Hospital (IT), Tampere University Hospital (FI), Cancer Research Center (US), Tampere University (FI), Hôpital Raymond-Poincaré (FR), SickKids Foundation (CA), Perron Institute for Neurological and Translational Science (AU), Murdoch Children's Research Institute (AU), National Hospital for Neurology and Neurosurgery (GB), Hospital San Borja Arriarán (CL), Avenir Health (US), Centre de Recherche en Myologie, University College London (GB), University of Manitoba (CA), New York University (US), Hacettepe University (TR), University of Chile (CL), University of Hong Kong (HK), University of Latvia (LV), University of Bologna (IT)
Good health and well-being
Openalex Percentile: Top 30%
Muscle Physiology and Disorders
0.81
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.