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Article

Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene

1
Neurology Unit, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
2
Neuromuscular and Rare Disease Unit, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
3
Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
4
Unit of Neuroradiology, Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy
5
Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
*
Author to whom correspondence should be addressed.
Academic Editors: Konrad Huppi and Kunihiro Tsuchida
Int. J. Mol. Sci. 2022, 23(17), 9817; https://doi.org/10.3390/ijms23179817
Received: 31 May 2022 / Revised: 11 August 2022 / Accepted: 24 August 2022 / Published: 29 August 2022
(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))
Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogenous presentations displaying predominantly proximal muscle weakness due to the loss of skeletal muscle fibers. Beta-sarcoglycanopathy (LGMDR4) results from biallelic molecular defects in SGCB and features pediatric onset with limb-girdle involvement, often complicated by respiratory and heart dysfunction. Here we describe a patient who presented at the age of 12 years reporting high creatine kinase levels and onset of cramps after strenuous exercise. Instrumental investigations, including a muscle biopsy, pointed towards a diagnosis of beta-sarcoglycanopathy. NGS panel sequencing identified two variants in the SGCB gene, one of which (c.243+1548T>C) was found to promote the inclusion of a pseudoexon between exons 2 and 3 in the SGCB transcript. Interestingly, we detected the same genotype in a previously reported LGMDR4 patient, deceased more than twenty years ago, who had escaped molecular diagnosis so far. After the delivery of morpholino oligomers targeting the pseudoexon in patient-specific induced pluripotent stem cells, we observed the correction of the physiological splicing and partial restoration of protein levels. Our findings prompt the analysis of the c.243+1548T>C variant in suspected LGMDR4 patients, especially those harbouring monoallelic SGCB variants, and provide a further example of the efficacy of antisense technology for the correction of molecular defects resulting in splicing abnormalities. View Full-Text
Keywords: LGMD; SGCB; beta-sarcoglycan; morpholino LGMD; SGCB; beta-sarcoglycan; morpholino
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MDPI and ACS Style

Magri, F.; Zanotti, S.; Salani, S.; Fortunato, F.; Ciscato, P.; Gerevini, S.; Maggi, L.; Sciacco, M.; Moggio, M.; Corti, S.; Bresolin, N.; Comi, G.P.; Ronchi, D. Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene. Int. J. Mol. Sci. 2022, 23, 9817. https://doi.org/10.3390/ijms23179817

AMA Style

Magri F, Zanotti S, Salani S, Fortunato F, Ciscato P, Gerevini S, Maggi L, Sciacco M, Moggio M, Corti S, Bresolin N, Comi GP, Ronchi D. Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene. International Journal of Molecular Sciences. 2022; 23(17):9817. https://doi.org/10.3390/ijms23179817

Chicago/Turabian Style

Magri, Francesca, Simona Zanotti, Sabrina Salani, Francesco Fortunato, Patrizia Ciscato, Simonetta Gerevini, Lorenzo Maggi, Monica Sciacco, Maurizio Moggio, Stefania Corti, Nereo Bresolin, Giacomo Pietro Comi, and Dario Ronchi. 2022. "Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene" International Journal of Molecular Sciences 23, no. 17: 9817. https://doi.org/10.3390/ijms23179817

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