SNUPN-Related Muscular Dystrophy: novel phenotypic, pathological and functional protein insights

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dc.contributor.authorMuelas Gómez, Nuria
dc.contributor.authorIruzubieta Agudo, Pablo
dc.contributor.authorDamborenea Moreno, Alberto
dc.contributor.authorPérez-Fernandez, Laura
dc.contributor.authorAzorín, Inmaculada
dc.contributor.authorJiménez García, Juan Carlos
dc.contributor.authorTöpf, Ana
dc.contributor.authorMartí, Pilar
dc.contributor.authorFores-Toribio, Lorena
dc.contributor.authorManterola, María
dc.contributor.authorBlanco Máñez, Rosana
dc.contributor.authorPikatza-Menoio, Oihane
dc.contributor.authorAlonso-Martin, Sonia
dc.contributor.authorStraub, Volker
dc.contributor.authorLópez Cortajarena, Aitziber
dc.contributor.authorLópez de Munain Arregui, Adolfo
dc.contributor.authorDe Sancho, David
dc.contributor.authorBlázquez García, Lorea
dc.contributor.authorVílchez, Juan J.
dc.date.accessioned2026-02-27T11:37:49Z
dc.date.available2026-02-27T11:37:49Z
dc.date.issued2026-02-01
dc.date.updated2026-02-27T11:37:49Z
dc.description.abstractObjective: SNUPN-related muscular dystrophy or LGMDR29 is a new entity that covers from a congenital or childhood onset pure muscular dystrophy to more complex phenotypes combining neurodevelopmental features, cataracts, or spinocerebellar ataxia. So far, 12 different variants have been described. Here we report the first family with SNUPN-related muscular dystrophy presenting an adult-onset myopathy as well as novel ultrastructural findings. Methods: Clinical evaluation, muscle and brain magnetic resonance imaging (MRI), and muscle histopathological and electron microscopy analysis were conducted. Functional studies including protein modelling and interaction, immunofluorescence and splicing analysis were also performed. Results: Two siblings carrying two novel deleterious variants in the SNUPN gene (p.Arg27Cys and p.Cys174Tyr) showed adult-onset proximo-distal and axial muscle weakness with early respiratory involvement. One patient presented with asymptomatic cerebellar atrophy. Muscle MRI identified involvement in the paravertebral, triceps brachii, sartorius and gracilis muscles. The histopathology revealed dystrophic changes and an abnormal pattern of cytoskeletal and myofibrillar proteins, while electron microscopy disclosed the proliferation of granules and vesicles associated with features of nuclear envelope and sarcolemma remodelling. Functional studies showed that SNUPN variants impair snurportin-1 function through reduced binding affinity to importin-β and impaired folding, leading to disturbed nuclear import of small nuclear ribonucleoproteins and downstream splicing. Interpretation: Our work expands the phenotype of SNUPN-related muscular dystrophy and provides more insights into their pathological profile. We advise SNUPN testing in patients with late-onset proximo-distal and axial weakness with early respiratory impairment and features reminding inclusion body myositis (IBM). Granular deposits suggestive of biomolecular condensates perturbed cell organelle traffic and membrane homeostasis, opening new avenues to understand the pathomechanisms involved in this novel disease.en
dc.description.sponsorshipThis study was funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, through projects PI21/01532(awarded to NM), PI19/00468 and PI22/00598 (awarded to LB), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas(CIBERNED) y Enfermedades Raras (CIBERER) and a funding agreement between Fundación Isabel Gemio (Madrid, Spain) and IIS La Fe to supportresearch on Rare Neuromuscular Disorders and the Valencian Council for Education, Culture, University and Employment (PROMETEO/2023/053) and PROMETEO/2019/075 (awarded to NM). This research was also supported by the Spanish Ministry of Science and Innovation through Programa Fortalece (FORT23/00026) (awarded to SAM), PID2021-127907NB-I00 MINECO project, awarded to DSS, and Ramon y Cajal contract RYC2018-024397-I, awarded to LB and funded by MICIU/AEI. ALC. acknowledges support by the Agencia Estatal de Investigación, grant PID2022-137977OB-I00(ProTHER) funded by MCIN/AEI/10.13039/501100011033. This work was performed under the Maria de Maeztu Units of Excellence Program fromthe Spanish State Research Agency—Grant No. MDM-2017- 0720. The Basque Government and the Basque Foundation for Science supported thisstudy through IT1584-22 project to DDS, IKUR strategy NEURODEGENPROT project to ALM, RF/2019/001 IKERBASQUE fellowship to LB and PRE_2022_2_0224 Doctoral Training fellowship to AD and PRE_2019_1_0339 to OPM. AT and VS were supported by the NIHR Newcastle BiomedicalResearch Centreen
dc.identifier.citationMuelas, N., Iruzubieta, P., Damborenea, A., Pérez-Fernández, L., Azorín, I., Jiménez García, J. C., Töpf, A., Martí, P., Fores-Toribio, L., Manterola, M., Blanco-Mañez, R., Pikatza-Menoio, O., Alonso-Martín, S., Straub, V., Cortajarena, A. L., López de Munain, A., De Sancho, D., Blázquez, L., & Vilchez, J. J. (2026). SNUPN-Related Muscular Dystrophy: novel phenotypic, pathological and functional protein insights. Annals of Clinical and Translational Neurology, 13(2), 285-295. https://doi.org/10.1002/ACN3.70211
dc.identifier.doi10.1002/ACN3.70211
dc.identifier.eissn2328-9503
dc.identifier.urihttps://hdl.handle.net/20.500.14454/5283
dc.language.isoeng
dc.publisherJohn Wiley and Sons Inc
dc.rights© 2025 The Author(s)
dc.subject.otherInclusion body myositis (IBM)
dc.subject.otherMuscular dystrophy
dc.subject.otherNeurogenetics
dc.subject.otherSNUPN
dc.subject.otherSnurportin-1
dc.subject.otherSplicing
dc.titleSNUPN-Related Muscular Dystrophy: novel phenotypic, pathological and functional protein insightsen
dc.typejournal article
dcterms.accessRightsopen access
oaire.citation.endPage295
oaire.citation.issue2
oaire.citation.startPage285
oaire.citation.titleAnnals of Clinical and Translational Neurology
oaire.citation.volume13
oaire.licenseConditionhttps://creativecommons.org/licenses/by/4.0/
oaire.versionVoR
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