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August 2024
Alterations 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.
2024
Iruzubieta 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 MC, Müller-Felber W, Thiele S, Moragón S, Bastida-Lertxundi N, López-Cortajarena A, Elortza F, Gereñu G, Alonso-Martin S, Straub V, de Sancho D, Teleanu R, López de Munain A, Blázquez L. Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features. Brain. 2024 Feb 15:awae046. doi: 10.1093/brain/awae046. *First co-authors. Quality indexes: Impact Factor 14.5. 1st decil in Neurosciences rank by JCI (7/306). Source JCR 2022.
Currò R, Dominik N, Facchini S, Vegezzi E, Sullivan R, Galassi Deforie V, Fernández-Eulate G, Traschütz A, Rossi S, Garibaldi M, Kwarciany M, Taroni F, Brusco A, Good JM, Cavalcanti F, Hammans S, Ravenscroft G, Roxburgh RH; RFC1 repeat expansion study group; Parolin Schnekenberg R, Rugginini B, Abati E, Manini A, Quartesan I, Ghia A, Lòpez de Munaìn A, Manganelli F, Kennerson M, Santorelli FM, Infante J, Marques W, Jokela M, Murphy SM, Mandich P, Fabrizi GM, Briani C, Gosal D, Pareyson D, Ferrari A, Prados F, Yousry T, Khurana V, Kuo SH, Miller J, Troakes C, Jaunmuktane Z, Giunti P, Hartmann A, Basak N, Synofzik M, Stojkovic T, Hadjivassiliou M, Reilly MM, Houlden H, Cortese A (2024). Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease. Brain. doi: 10.1093/brain/awad43
Kartanou C, Mitrousias A, Pellerin D, Kontogeorgiou Z, Iruzubieta P, Dicaire MJ, Danzi MC, Koniari C, Athanassopoulos K, Panas M, Stefanis L, Zuchner S, Brais B, Houlden H, Karadima G, Koutsis G. The FGF14 GAA repeat expansion in Greek patients with late-onset cerebellar ataxia and an overview of the SCA27B phenotype across populations. Clin Genet. 2024 Jan 14. doi: 10.1111/cge.14482.
López de Munain A, Iruzubieta P, Pujol A, Blázquez L. Title: Neurogenética fundamental. Book chapter in Neurología. 7th edition. 2024. Edited by Juan José Zarranz. ISBN: 9788491130710. Publisher: Elsevier Limited (UK). https://elsevierebooks.vitalsource.com/books/9788413827247
2023
Iruzubieta P, Pellerin D, Bergareche A, Albajar I, Mondragón E, Vinagre A, Fernández-Torrón R, Moreno F, Equiza J, Campo-Caballero D, Poza JJ, Ruibal M, Formica A, Dicaire MJ, Danzi MC, Zuchner S, Croitoru I, Ruiz M, Schlüter A, Casasnovas C, Pujol A, Brais B, Houlden H, de Munain AL, Ruiz-Martínez J.Frequency and phenotypic spectrum of spinocerebellar ataxia 27B and other genetic ataxias in a Spanish cohort of late-onset cerebellar ataxia.European Journal of Neurology.. 2023 Aug 14. doi: 10.1111/ene.16039. Online ahead of print.PMID: 37578187.
Rovira, E., Moreno, B., Razquin, N., Blázquez, L., Hernández-Alcoceba, R., Fortes, P., & Pastor, F. Title: Engineering U1-Based Tetracycline-Inducible Riboswitches to Control Gene Expression in Mammals. Journal: ACS nano, 17(23), 23331–23346. 2023. Quality indexes: Impact Factor 17.1. 1st decil in Chemistry, Multidisciplinary rank by JCI (13/230). Source JCR 2022. https://doi.org/10.1021/acsnano.3c01994
Novis, L. E., Frezatti, R. S., Pellerin, D., Tomaselli, P. J., Alavi, S., Della Coleta, M. V., Spitz, M., Dicaire, M.-J., Iruzubieta, P., Pedroso, J. L., Barsottini, O., Cortese, A., Danzi, M. C., França, M. C., Brais, B., Zuchner, S., Houlden, H., Raskin, S., Marques, W., &Teive, H. A. (2023). Frequency of gaa-fgf14ataxia in a large cohort of Brazilian patients with unsolved adult-onset cerebellar ataxia. NeurologyGenetics, 9(5). https://doi.org/10.1212/nxg.0000000000200094
Bonnet, C., Pellerin, D., Roth, V., Clément, G., Wandzel, M., Lambert, L., Frismand, S., Douarinou, M., Grosset, A., Bekkour, I., Weber, F., Girardier, F., Robin, C., Cacciatore, S., Bronner, M., Pourié, C., Dreumont, N., Puisieux, S., Iruzubieta, P., … Renaud, M. (2023). Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B. Scientific Reports, 13(1), 1–11. https://doi.org/10.1038/s41598-023-36654-8.
Pellerin, D., Iruzubieta, P., Tekgül, Ş., Danzi, M. C., Ashton, C., Dicaire, M., Wandzel, M., Roth, V., Lamont, P. J., Bonnet, C., Renaud, M., Synofzik, M., Zuchner, S., Brais, B., Başak, N. A., & Houlden, H. (2023). Non‐GAA Repeat Expansions in FGF14 Are Likely Not Pathogenic—Reply to: “Shaking Up Ataxia: FGF14 and RFC1 Repeat Expansions in Affected and Unaffected Members of a Chilean Fam. Movement Disorders, 38(8), 1575–1577. https://doi.org/10.1002/mds.29552. IF 8.6 (2022). Q1 Clinical Neurology.
Baselga, M., Iruzubieta, P., Castiella, T., Monzón, M., Monleón, E., Berga, C., Schuhmacher, A. J., & Junquera, C. (2023). Spheresomes are the main extracellular vesicles in low-grade gliomas. Scientific Reports, 13(1), 11180.https://doi.org/10.1038/s41598-023-38084-y.
Beltrán-Corbellini, Á., Romeral-Jiménez, M., Mayo, P., Sánchez-Miranda Román, I., Iruzubieta, P., Chico-García, J. L., Parra-Díaz, P., García-Morales, I., Toledano, R., Aledo-Serrano, Á., & Gil-Nagel, A. (2023). Cenobamate in patients with highly refractory focal epilepsy: A retrospective real-world study. Seizure: European Journal of Epilepsy, 111(July), 71–77. https://doi.org/10.1016/j.seizure.2023.07.026.
Quartesan, I., Vegezzi, E., Currò, R., Heslegrave, A., Pisciotta, C., Iruzubieta, P., Salvalaggio, A., Fernandez-Eulate, G., Dominik, N., Rugginini, B., Manini, A., Abati, E., Facchini, S., Manso, K., Albajar, I., Laban, R., Rossor, A., Pichiecchio, A., Cosentino, G., Saveri, P., Salsano, E., Andreetta, F., Valente, E., Zetterberg, H., Giunti, P., Stojkovic, T., Briani, C., Lopez de Munain, A., Pareyson, D., Reilly, M., Houlden, H., Tassorelli, C., & Cortese, A. (2023). Serum Neurofilament Light Chain in Replication Factor Complex Subunit 1 CANVAS and Disease Spectrum. Movement Disorders Dec 6. doi: 10.1002/mds.29680.
Mas AM, Goñi E, Ruiz de Los Mozos I, Arcas A, Statello L, González J, Blázquez L, Lee WTC, Gupta D, Sejas Á, Hoshina S, Armaos A, Tartaglia GG, Waga S, Ule J, Rothenberg E, Gómez M, Huarte M. Title: ORC1 binds to cis-transcribed RNAs for efficient activation of replication origins. Journal: Nat Comms, Jul 24;14(1):4447. 2023 Quality indexes: Impact Factor 16.6. 1st decil in Multidisciplinary Sciences rank by JCI (7/134). Source JCR 2022. https://doi:10.1038/s41467-023-40105-3
Barreiro RAS, Guardia GDA, Meliso FM, Lei X, Li WQ, Savio A, Fellermeyer M, Conceição HB, Mercuri RLV, Landry T, Qiao M, Blazquez L, Ule J, Penalva LOF, Galante PAF. Title: The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes. Journal: RNA Biol, Jan;20(1):311-322. 2023 Quality indexes: Impact Factor 4.1. 2ndquartile in Biochemistry and Molecular Biology rank by JCI (151/315). Source JCR 2022. https://doi:10.1101/2022.12.20.521107
2022
Prats-Sánchez L, Iruzubieta P, Vesperinas A, Collet R , Martínez-Domeño A, Guisado-Alonso D, Camps-Renom P, Delgado-Mederos R, Guasch-Jiménez M, Ramos-Pachón A, Rodríguez-Antigüedad J, Campo-Caballero D, Equiza J, de la Riva P, Martínez-Zabaleta M, de Arce A, Martí-Fàbregas J. Frequency, Predictors, Etiology, and Outcomes for Deep Intracerebral Hemorrhage without Hypertension. J Stroke Cerebrovasc Dis. 2022 Jan 8;31(3):106293. DOI: 10.1016/j.jstrokecerebrovasdis.2021.106293.
Equiza J, de la Riva P, Larrea JA, Marta-Enguita J, Albájar I, Lüttich A, Garmendia E, Alonso M, de Arce A, Díez N, Gonzalez F, Iruzubieta P, Sulibarria N, Puig J, Martínez-Zabaleta M. Impact on functional outcome of an adaptive Stroke Unit based system of care for patients undergoing endovascular treatment during pandemic times. European Stroke Journal.
Rovira E, Moreno B, Razquin N, Hjerpe R, Gonzalez-Lopez M, Barrio R, Ruiz de Los Mozos I, Ule J, Pastor F, Blazquez LCA, Fortes PCA. Title: U1A is a positive regulator of the expression of heterologous and cellular genes involved in cell proliferation and migration. Molecular Therapy – Nucleic Acids, May 10;28:831-846. 2022 Quality indexes: Impact Factor 8.8. 1st decil in Medicine, Research and Experimental rank by JCI (12/190). Source JCR 2022. https://doi.org/10.1016/j.omtn.2022.05.023.
2021
Iruzubieta, P., Castiella, T., Monleón, E., Berga, C., Muñoz, G., & Junquera, C. (2021). Primary cilia presence and implications in bladder cancer progression and invasiveness. Histochemistry and Cell Biology, 0123456789.https://doi.org/10.1007/s00418-021-01965-2. FI 3,418. Q1 Microscopy Q3 Cell Biology (2019); FI 4,304. Q1 Microscopy Q3 Cell Biology (2020)
Iruzubieta, P., Campo-Caballero, D., Equiza, J., Albajar, I., Sulibarría, N., Sáez, R., Andrés, N., Mondragón, E., Zulaica, M., de Arce, A., Urtasun, M., & López de Munain, A. (2021). Description of Two Families with New Mutations in Familial Cerebral Cavernous Malformations Genes. Journal of Stroke and Cerebrovascular Diseases, 30(12), 106130. https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.106130. FI 2,136 Q4 Neurosciences, Q4 Peripheral vascular disease (2020) FI 2.667 Q4 Neurosciences, Q3 Peripheral vascular disease (2021)
Castiella, T.*, Iruzubieta,P.*, Monleon, E., Cardiel, M.J., Gómez-Vallejo, J., Monzón, M., Junquera, C. Stromal cells of giant cell tumor of bone show primary cilia in giant cell tumor of bone. Microscopy Research and Technique. 2021 Nov 10.doi: 10.1002/jemt.23976. *First co-authors.
Equiza, J., Rodríguez-Antigüedad, J., Campo-Caballero, D., Iruzubieta Agudo, P., Ruibal, M., De La Riva, P., Garmendia, E., & Mínguez-Olaondo, A. (2021). Pituitary apoplexy causing thunderclap headache: Easy to miss. Practical Neurology, 21(2), 169–170. https://doi.org/10.1136/practneurol-2020-002625.
Equiza, J., Campo-Caballero, D., Rodríguez-Antigüedad, J., Iruzubieta, P., Vinagre-Aragón, A., Echeverria, J., Imaz, N., Alberdi, T., López de Munain, A., Urtasun, M., & Espinal, J. B. (2021). Management of an outbreak of botulism with benign clinical presentation. Journal of Clinical Neuroscience, 88, 159–162.https://doi.org/10.1016/j.jocn.2021.03.041.
Equiza, J., Rodríguez-Antigüedad, J., Campo-Caballero, D., Iruzubieta, P., Prada, Á., Roncancio, A., Fernández, E., Ganzarain Oyarbide, M., Arruti, M., Urtasun, M. A., & Castillo-Triviño, T. (2021). Autoimmune GFAP astrocytopathy presenting with remarkable CNS hyperexcitability and oculogyric crises. Journal of Neuroimmunology, 359(May), 10–12. https://doi.org/10.1016/j.jneuroim.2021.577695.
Sakellariou D, Tiberti M, Kleiber TH, Blazquez L, López AR, Abildgaard MH, Lubas M, Bartek J, Papaleo E, Frankel LB. Title: eIF4A3 regulates the TFEB-mediated transcriptional response via GSK3B to control autophagy Journal: Cell Death Diff, Dec;28(12):3344-3356. 2021 Quality indexes: Impact Factor 12.4. 1st decil in Biochemistry and Molecular Biology rank by JCI (18/315). Source JCR 2022. https://doi.org/10.1038/s41418-021-00822-y
2020
Iruzubieta, P., Monzón, M., Castiella, T., Ramírez, T., & Junquera, C. (2020). Hedgehog signalling pathway activation in gastrointestinal stromal tumours is mediated by primary cilia. Gastric Cancer, 23(1), 64–72.https://doi.org/10.1007/s10120-019-00984-2.
Iruzubieta, P., Cantarero, I., Monzón, M., Lahoz, M., & Junquera, C. (2020). Supporting Evidence of Human Enteric Nervous System Adult Neurogenesis: Presence of Primary Cilia and Adult Neurogenesis Markers. Cellular and Molecular Neurobiology. https://doi.org/10.1007/s10571-020-01017-8.
Campo-Caballero, David, Rodriguez-Antigüedad, J., Ekiza-Bazan, J., Iruzubieta-Agudo, P., Fernández-Eulate, G., Muñoz-Lopetegui, A., Martínez-Zabaleta, M., de la Riva, P., Urtasun-Ocariz, M., de Munain, A. L., & de Arce, A. (2020). COL4A1 Mutation as a Cause of Familial Recurrent Intracerebral Hemorrhage. Journal of Stroke and Cerebrovascular Diseases, 29(4), 1–2. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104652.
Campo-Caballero, D., de la Riva, P., de Arce, A., Martínez-Zabaleta, M., Rodríguez-Antigüedad, J., Ekiza, J., Iruzubieta, P., Purroy, F., Fuentes, B., de Lera Alfonso, M., Krupinski, J., Mengual Chirife, J. J., Palomeras, E., Guisado-Alonso, D., Rodríguez-Yáñez, M., Ustrell, X., Tejada García, J., de Felipe Mimbrera, A., Paré-Curell, M., … Serena, J. (2020). Tratamiento de reperfusión en el ictus isquémico agudo por disección arterial cervicocerebral: descripción de los resultados de un estudio nacional multicéntrico. Neurología, xxxx. https://doi.org/10.1016/j.nrl.2020.10.016
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