Examinando por Autor "Iruzubieta Agudo, Pablo"

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    Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia
    (John Wiley and Sons Inc, 2025-01) Launay, Nathalie; Espinosa Alcantud, Maria Dolores; Verdura, Edgar; Fernández García de Eulate, Gorka; Ondaro Ezkurra, Jon; Iruzubieta Agudo, Pablo; Marsal Terés, María; Schlüter, Agatha; Ruiz Sales, Montserrat; Fourcade, Stèphane; Rodríguez-Palmero Seuma, Agustí; Zulaica, Miren; Sistiaga Berrondo, Andone; Labayru, Garazi; Loza-Alvarez, Pablo; Vaquero, Alejandro; López de Munain Arregui, Adolfo; Pujol, Aurora
    Senescence, marked by permanent cell cycle arrest may contribute to the decline in regenerative potential and neuronal function, thereby promoting neurodegenerative disorders. In this study, we employed whole exome sequencing to identify a previously unreported biallelic missense variant in SVBP (p.Leu49Pro) in six patients from three unrelated families. These affected individuals present with a complex hereditary spastic paraplegia (HSP), peripheral neuropathy, verbal apraxia, and intellectual disability, exhibiting a milder phenotype compared to patients with nonsense SVBP mutations described previously. Consistent with SVBP's primary role as a chaperone necessary for VASH-mediated tubulin detyrosination, both patient fibroblasts with the p.Leu49Pro mutation, and HeLa cells harboring an SVBP knockdown exhibit microtubule dynamic instability and alterations in pericentriolar material (PCM) component trafficking and centrosome cohesion. In patient fibroblasts, structural abnormalities in the centrosome trigger mitotic errors and cellular senescence. Notably, premature senescence characterized by elevated levels of p16INK4, was also observed in patient peripheral blood mononuclear cells (PBMCs). Taken together, our findings underscore the critical role of SVBP in the development and maintenance of the central nervous system, providing novel insights associating cytokinesis failure with cortical motor neuron disease and intellectual disability.
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    Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features
    (Oxford University Press, 2024-08) Iruzubieta Agudo, Pablo; Damborenea Moreno, Alberto; Ioghen, Mihaela; Bajew, Simon; Fernández Torrón, Roberto; Töpf, Ana; Herrero Reiriz, Álvaro; Epure, Diana; Vill, Katharina; Hernández Laín, A.; Manterola Larrañaga, María; Azkargorta, Mikel; Pikatza-Menoio, Oihane; Pérez-Fernandez, Laura; García Puga, Mikel; Gaina, Gisela; Bastian, Alexandra; Streata, Ioana; Walter, Maggie C.; Müller-Felber, Wolfgang; Thiele, Simone; Moragón Rodríguez, Saioa; Bastida Lertxundi, Nerea; López Cortajarena, Aitziber; Elortza, Felix; Gereñu Lopetegi, Gorka; Alonso-Martin, Sonia; Straub, Volker; Sacho, David de; Teleanu, Raluca; López de Munain Arregui, Adolfo; Blázquez García, Lorea
    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.
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    A founder variant in the RYR1 gene is associated with hyperCKemia, myalgia and muscle cramps
    (John Wiley and Sons Inc, 2025-01) Segarra Casas, Alba; Iruzubieta Agudo, Pablo; Kapetanovic García, Solange; Hernández Laín, A.; Jericó Pascual, Ivonne; Fernández Torrón, Roberto; Maneiro, Miren; Marco Moreno, Pablo; Zelaya Huerta, María Victoria; Rodríguez Santiago, Benjamín; Calafell Majó, Francesc; Töpf, Ana; Straub, Volker; Vallejo Illarramendi, Ainara; López de Munain Arregui, Adolfo; Gallano Petit, María Pía; González Quereda, Lidia
    Background and purpose: Pathogenic variants in the RYR1 gene have been associated with a variety of conditions, ranging from congenital myopathy to adult manifestations. Our aim was to characterize the p.Leu2286Val variant in 17 Basque patients, to accurately determine its correlation with clinical features and to explore the possible founder effect of the variant. Methods: Families harbouring the p.Leu2286 RYR1 variant underwent a detailed clinical evaluation, including muscle magnetic resonance imaging, electromyography and muscle biopsy. Haplotypes were analysed in available patients and their relatives. Results: Individuals carrying the p.Leu2286Val shared a common haplotype, suggesting a founder event in the Basque Country population. The most prevalent features were exertional myalgia, high creatine kinase (CK) levels, cramps and muscle hypertrophy. None of the patients carrying only the p.Leu2286Val showed progression to severe muscle weakness and muscle magnetic resonance imaging showed a heterogeneous muscle involvement. Muscle biopsy revealed non-specific findings in two patients and features associated with central core disease in one patient carrying only the p.Leu2286Val and two patients harbouring an additional RYR1 variant. Three individuals carrying an in trans RYR1 variant presented with an earlier onset and more severe phenotype. Conclusion: Here, it is shown that the dominantly inherited p.Leu2286Val RYR1 founder variant is associated with a milder phenotype of exercise intolerance, myalgia and hyperCKemia.
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    The role of integrin β1D mislocalization in the pathophysiology of calpain 3-related limb–girdle muscular dystrophy
    (Multidisciplinary Digital Publishing Institute (MDPI), 2025-03) Valls Rodríguez, Andrea; Ruiz Roldán, Cristina; Immanuel, Jenita; Alonso-Martin, Sonia; Gallardo, Eduard; Fernández Torrón, Roberto; Bonilla Zagala, Mario; Lersundi Artamendi, Ana; Hernández Laín, A.; Domínguez González, Cristina; Vílchez, Juan J.; Iruzubieta Agudo, Pablo; López de Munain Arregui, Adolfo; Sáenz, Amets
    Limb–girdle muscular dystrophy R1 (LGMDR1) is characterized by progressive proximal muscle weakness due to mutations in the CAPN3 gene. Little is known about CAPN3’s function in muscle, but its loss results in aberrant sarcomere formation. Human muscle structure was analyzed in this study, with observations including integrin β1D isoform (ITGβ1D) mislocalization, a lack of Talin-1 (TLN1) in the sarcolemma and the irregular expression of focal adhesion kinase (FAK) in LGMDR1 muscles, suggesting a lack of integrin activation with an altered sarcolemma, extracellular matrix (ECM) assembly and signaling pathway deregulation, which may cause frailty in LGMDR1 muscle fibers. Additionally, altered nuclear morphology, centrosome distribution and microtubule organization have been found in muscle cells derived from LGMDR1 patients