Examinando por Autor "Alonso-Martin, Sonia"

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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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    Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis
    (Springer Science and Business Media Deutschland GmbH, 2024-09-16) Zufiría García, Mónica; Pikatza-Menoio, Oihane; Garciandia Arcelus, Maddi; Bengoetxea Bausela, Xabier; Jiménez Zúñiga, Andrés; Elicegui, Amaia; Levchuk, María; Arnold García, Olatz; Ondaro Ezkurra, Jon; Iruzubieta Agudo, Pablo; Rodríguez Gómez, Laura; Fernández Pelayo, Uxoa; Muñoz Oreja, Mikel; Aiastui Pujana, Ana; García Verdugo, Jose Manuel; Herranz Pérez, Vicente; Zulaica, Miren; Poza Aldea, Juan José; Ruiz Onandi, Rebeca; Fernández Torrón, Roberto; Espinal Valencia, Juan Bautista; Bonilla Zagala, Mario; Lersundi Artamendi, Ana; Fernández-Eulate, Gorka; Riancho Zarrabeitia, Javier; Vallejo Illarramendi, Ainara; Holt, Ian James; Sáenz, Amets; Malfatti, Edoardo; Duguez, Stéphanie; Blázquez García, Lorea; López de Munain Arregui, Adolfo; Gereñu Lopetegi, Gorka; Gil Bea, Francisco Javier; Alonso-Martin, Sonia
    Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.
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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
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    SNUPN-Related Muscular Dystrophy: novel phenotypic, pathological and functional protein insights
    (John Wiley and Sons Inc, 2026-02-01) Muelas Gómez, Nuria; Iruzubieta Agudo, Pablo ; Damborenea Moreno, Alberto ; Pérez-Fernandez, Laura ; Azorín, Inmaculada; Jiménez García, Juan Carlos; Töpf, Ana; Martí, Pilar; Fores-Toribio, Lorena; Manterola, María; Blanco Máñez, Rosana ; Pikatza-Menoio, Oihane ; Alonso-Martin, Sonia ; Straub, Volker ; López Cortajarena, Aitziber; López de Munain Arregui, Adolfo ; De Sancho, David; Blázquez García, Lorea ; Vílchez, Juan J.
    Objective: 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.