Journal article
Characterization of severe COL6-related dystrophy due to the recurrent variant COL6A1 c.930+189C>T
Brain (London, England : 1878), Vol.148(9), pp.3215-3227
09/03/2025
DOI: 10.1093/brain/awaf116
PMCID: PMC12404708
PMID: 40177858
Abstract
Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised 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 COL6-RD, 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 characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen 6 genes. Patients manifest a consistently severe phenotype characterised 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.
Details
- Title: Subtitle
- Characterization of severe COL6-related dystrophy due to the recurrent variant COL6A1 c.930+189C>T
- Creators
- A Reghan Foley - National Institute of Neurological Disorders and StrokeVéronique Bolduc - National Institute of Neurological Disorders and StrokeFady Guirguis - National Institute of Neurological Disorders and StrokeSandra Donkervoort - National Institute of Neurological Disorders and StrokeYing Hu - National Institute of Neurological Disorders and StrokeRotem Orbach - Dana (United Kingdom)Riley M McCarty - National Institute of Neurological Disorders and StrokeApurva Sarathy - National Institute of Neurological Disorders and StrokeGina Norato - National Institute of Neurological Disorders and StrokeBeryl B Cummings - Broad InstituteMonkol Lek - Broad InstituteAnna Sarkozy - Great Ormond Street HospitalRussell J Butterfield - University of UtahJanbernd Kirschner - University of FreiburgAndrés Nascimento - Institut de Recerca Sant Joan de DéuDaniel Natera-de Benito - Institut de Recerca Sant Joan de DéuSusana Quijano-Roy - Garches Neuromuscular Reference Center, Child Neurology and ICU Department, APHP Raymond Poincare University Hospital (UVSQ Paris Saclay), Garches 92380, FranceTanya Stojkovic - Assistance Publique – Hôpitaux de ParisLuciano Merlini - University of BolognaGiacomo Comi - Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMonique Ryan - Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, AustraliaDenise McDonald - Department of Neurodisability, Children's Health Ireland at Tallaght, Dublin 24 IrelandPinki Munot - Great Ormond Street HospitalGrace Yoon - University of TorontoEdward Leung - University of ManitobaErika Finanger - Oregon Health & Science UniversityMeganne E Leach - Oregon Health & Science UniversityJames Collins - Cincinnati Children's Hospital Medical CenterCuixia Tian - Cincinnati Children's Hospital Medical CenterPayam Mohassel - National Institute of Neurological Disorders and StrokeSarah B Neuhaus - National Institute of Neurological Disorders and StrokeDimah Saade - National Institute of Neurological Disorders and StrokeBenjamin T Cocanougher - Duke UniversityMary-Lynn Chu - Department of Neurology, New York University School of Medicine, New York, NY 10016, USAMena Scavina - Division of Neurology, Nemours Children's Hospital Delaware, Wilmington, DE 19803, USACarla Grosmann - University of California San DiegoRandal Richardson - Gillette Children's Specialty HealthcareBrian D Kossak - Dartmouth–Hitchcock Medical CenterSidney M Gospe Jr - University of WashingtonVikram Bhise - Rutgers, The State University of New JerseyGita Taurina - Children's Clinical University Hospital, Medical Genetics and Prenatal Diagnostic Clinic, Riga 1004, LatviaBaiba Lace - Riga East University HospitalMonica Troncoso - Pediatric Neuropsychiatry Service, Hospital Clínico San Borja Arriarán, Pediatric Department, Universidad de Chile, Santiago 1234, ChileMordechai Shohat - Sheba Medical CenterAdel Shalata - Bnai Zion Medical CenterSophelia H S Chan - University of Hong KongManu Jokela - Tampere University HospitalJohanna Palmio - Tampere University HospitalGöknur Haliloğlu - Hacettepe UniversityCristina Jou - Institut de Recerca Sant Joan de DéuCorine Gartioux - Centre de Recherche en MyologieHerimela Solomon-Degefa - University of CologneCarolin D Freiburg - University of CologneAlvise Schiavinato - University of CologneHaiyan Zhou - Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKSara Aguti - Neurodegenerative Disease Department, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UKYoram Nevo - Schneider Children's Medical CenterIchizo Nishino - National Center of Neurology and PsychiatryCecilia Jimenez-Mallebrera - Institut de Recerca Sant Joan de DéuShireen R Lamandé - The University of MelbourneValérie Allamand - Centre de Recherche en MyologieFrancesca Gualandi - Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara, Ferrara 44121, ItalyAlessandra Ferlini - Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara, Ferrara 44121, ItalyDaniel G MacArthur - Broad InstituteSteve D Wilton - Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands, WA 6009, AustraliaRaimund Wagener - University of CologneEnrico Bertini - Bambino Gesù Children's HospitalFrancesco Muntoni - Great Ormond Street HospitalCarsten G Bönnemann - National Institute of Neurological Disorders and Stroke
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.148(9), pp.3215-3227
- DOI
- 10.1093/brain/awaf116
- PMID
- 40177858
- PMCID
- PMC12404708
- NLM abbreviation
- Brain
- ISSN
- 1460-2156
- eISSN
- 1460-2156
- Publisher
- OXFORD UNIV PRESS; OXFORD
- Grant note
- NIH National Institute of Neurological Disorders and Stroke: 2025
We especially thank the patients and their families whose participation made this study possible. The thumbnail image for the online table of contents was created in BioRender. Or Bach, R. (2025) https://BioRender.com/oebrbvg.
- Language
- English
- Electronic publication date
- 04/03/2025
- Date published
- 09/03/2025
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984803810802771
Metrics
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