Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features

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dc.contributor.authorIruzubieta Agudo, Pablo
dc.contributor.authorDamborenea Moreno, Alberto
dc.contributor.authorIoghen, Mihaela
dc.contributor.authorBajew, Simon
dc.contributor.authorFernández Torrón, Roberto
dc.contributor.authorTöpf, Ana
dc.contributor.authorHerrero Reiriz, Álvaro
dc.contributor.authorEpure, Diana
dc.contributor.authorVill, Katharina
dc.contributor.authorHernández Laín, A.
dc.contributor.authorManterola Larrañaga, María
dc.contributor.authorAzkargorta, Mikel
dc.contributor.authorPikatza-Menoio, Oihane
dc.contributor.authorPérez-Fernandez, Laura
dc.contributor.authorGarcía Puga, Mikel
dc.contributor.authorGaina, Gisela
dc.contributor.authorBastian, Alexandra
dc.contributor.authorStreata, Ioana
dc.contributor.authorWalter, Maggie C.
dc.contributor.authorMüller-Felber, Wolfgang
dc.contributor.authorThiele, Simone
dc.contributor.authorMoragón Rodríguez, Saioa
dc.contributor.authorBastida Lertxundi, Nerea
dc.contributor.author López Cortajarena, Aitziber
dc.contributor.authorElortza, Felix
dc.contributor.authorGereñu Lopetegi, Gorka
dc.contributor.authorAlonso-Martin, Sonia
dc.contributor.authorStraub, Volker
dc.contributor.authorSacho, David de
dc.contributor.authorTeleanu, Raluca
dc.contributor.authorLópez de Munain Arregui, Adolfo
dc.contributor.authorBlázquez García, Lorea
dc.date.accessioned2025-03-10T13:47:47Z
dc.date.available2025-03-10T13:47:47Z
dc.date.issued2024-08
dc.date.updated2025-03-10T13:47:47Z
dc.description.abstractAlterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies, where mutations in genes involved in RNA metabolism or characterized by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle MRI, with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterized by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although inter-individual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganization. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients’ muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.en
dc.description.sponsorshipThis study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects PI19/00468 and PI22/00598 awarded to L.B., and co-funded by the European Union) and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED). This research was also supported by the Spanish Ministry of Science and Innovation and the Education Department of the Basque Government, through Ramon y Cajal (RYC2018-024397-I) and IKERBASQUE (RF/2019/001) fellowships respectively, awarded to L.B. A.D. is funded by Basque Government Doctoral Training Program (PRE_2022_2_0224). Financial support to D.D.S. comes from EuskoJaurlaritza (Basque Government) through the project IT1584-22, from the Spanish Ministry of Science and Innovation through the Office of Science Research (MINECO/FEDER) through grant PID2021- 127907NB-I00en
dc.identifier.citationIruzubieta, P., Damborenea, A., Ioghen, M., Bajew, S., Fernandez-Torrón, R., Töpf, A., Herrero-Reiriz, Á., Epure, D., Vill, K., Hernández-Laín, A., Manterola, M., Azkargorta, M., Pikatza-Menoio, O., Pérez-Fernandez, L., García-Puga, M., Gaina, G., Bastian, A., Streata, I., Walter, M. C., et al. (2024). Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features. Brain, 147(8), 2867-2883. https://doi.org/10.1093/BRAIN/AWAE046
dc.identifier.doi10.1093/BRAIN/AWAE046
dc.identifier.eissn1460-2156
dc.identifier.issn0006-8950
dc.identifier.urihttp://hdl.handle.net/20.500.14454/2500
dc.language.isoeng
dc.publisherOxford University Press
dc.rights© The Author(s) 2024
dc.subject.otherMyopathy
dc.subject.otherSmall-nuclear ribonucleoproteins (snRNPs)
dc.subject.otherSnurportin-1
dc.subject.otherSplicing
dc.titleBiallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like featuresen
dc.typejournal article
dcterms.accessRightsopen access
oaire.citation.endPage2883
oaire.citation.issue8
oaire.citation.startPage2867
oaire.citation.titleBrain
oaire.citation.volume147
oaire.licenseConditionhttps://creativecommons.org/licenses/by/4.0/
oaire.versionVoR
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