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Preprint
The recurrent deep intronic pseudoexon-inducing variant COL6A1 c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy
medRxiv : the preprint server for health sciences
Cold Spring Harbor Laboratory
2024
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 immunohistochemical 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 VI 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. Characterisation of this individual provides a robust validation for the development of our pseudoexon skipping therapy. 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 causative variant to a Bethlem muscular dystrophy phenotype.
Details
- Title
- The recurrent deep intronic pseudoexon-inducing variant COL6A1 c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy
- Authors/Creators
- A Reghan Foley - National Institute of Neurological Disorders and StrokeVéronique BolducFady GuirguisSandra DonkervoortYing HuRotem OrbachRiley M McCartyApurva SarathyGina NoratoBeryl B CummingsMonkol LekAnna SarkozyRussell J ButterfieldJanbernd KirschnerAndrés NascimentoDaniel Natera-de BenitoSusana Quijano-RoyTanya Stojkovic - Assistance Publique – Hôpitaux de ParisLuciano MerliniGiacomo ComiMonique RyanDenise McDonaldPinki MunotGrace YoonEdward LeungErika FinangerMeganne E LeachJames CollinsCuixia TianPayam MohasselSarah B NeuhausDimah SaadeBenjamin T CocanougherMary-Lynn ChuMena ScavinaCarla GrosmannRandal RichardsonBrian D KossakSidney M GospeVikram BhiseGita TaurinaBaiba LaceMonica TroncosoMordechai ShohatAdel ShalataSophelia H S ChanManu JokelaJohanna PalmioGöknur HaliloğluCristina JouCorine GartiouxHerimela Solomon-DegefaCarolin D FreiburgAlvise SchiavinatoHaiyan ZhouSara AgutiYoram NevoIchizo Nishino - National Center of Neurology and PsychiatryCecilia Jimenez-MallebreraShireen R LamandéValérie AllamandFrancesca GualandiAlessandra FerliniDaniel G MacArthur - Broad InstituteSteve D Wilton - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsRaimund WagenerEnrico BertiniFrancesco MuntoniCarsten G Bönnemann
- Publication Details
- medRxiv : the preprint server for health sciences
- Publisher
- Cold Spring Harbor Laboratory
- Identifiers
- 991005659469507891
- Copyright
- The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Preprint
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