19 results on '"Fabiola Mavillard"'
Search Results
2. NOVEL intronic CAPN3 Roma mutation alters splicing causing RNA mediated decay
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Fabiola Mavillard, Marcos Madruga‐Garrido, Eloy Rivas, Emilia Servián‐Morilla, Rainiero Ávila‐Polo, Irene Marcos, Francisco J. Morón, Carmen Paradas, and Macarena Cabrera‐Serrano
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract CAPN3 mutations cause a limb girdle muscular dystrophy. Functional characterization of novel mutations facilitates diagnosis of future cases. We have identified a novel (c.1992 + 2T>G) CAPN3 mutation that disrupts the donor splice site of intron 17 splicing out exon 17, with mRNA levels severely reduced or undetectable. The mutation induces a strong change in the 3D structure of the mRNA which supports no‐go mRNA decay as the probable mechanism for RNA degradation. The mutation was identified in two unrelated Roma individuals showing a common ancestral origin and founder effect. This is the first Roma CAPN3 mutation to be reported.
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- 2019
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3. Neuronal lipofuscinosis caused by Kufs disease/CLN4DNAJC5mutations but not by a CSPα/DNAJC5 deficiency
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Santiago López-Begines, Ángela Lavado-Roldán, Cristina Mesa-Cruz, Fabiola Mavillard, Nozha Borjini, Vera I. Wiersma, Carolina Aguado, Rafael Luján, Wiep Scheper, José L. Nieto-González, and Rafael Fernández-Chacón
- Abstract
Kufs disease/CLN4 is an autosomal dominant neurodegenerative disorder that affects young adults, caused by mutations in the DNAJC5 gene that encodes the synaptic vesicle co-chaperone Cysteine String Protein α (CSPα/DNAJC5). The Leu115Arg and Leu116Δ mutations in humans are known to independently cause the disease, although the underlying mechanisms are unknown. To investigate the disease mechanisms in vivo, we generated three independent mouse lines overexpressing different versions of CSPα/DNAJC5 under the neuron-specific Thy1 promoter: wild-type (WT), Leu115Arg, and Leu116Δ. Mice expressing mutant CSPα/DNAJC5 are viable and do not show any significant increase in morbidity or mortality. However, we observed the presence of pathological lipofuscinosis in the mutants, indicated by autofluorescent punctate structures labeled with antibodies against ATP synthase subunit C, which were absent in the WT transgenic line. Additionally, transmission electron microscopy revealed intracellular structures resembling granular osmiophilic deposits (GRODs), observed in Kufs disease patients, in the mutants but not in non-transgenic controls or the WT transgenic mice. Notably, conventional, or conditional knockout mice lacking CSPα/DNAJC5 did not exhibit any signs of increased lipofuscinosis or GRODs. Our novel mouse models thus provide a valuable tool to investigate the molecular mechanisms underlying Kufs disease/CLN4. We conclude that DNAJC5 mutations cause neuronal lipofuscinosis through a cell-autonomous gain of a novel but pathological function of CSPα/DNAJC5.
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- 2023
4. Anoctamin-5 related muscle disease: clinical and genetic findings in a large European cohort
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Alexander de Bruyn, Federica Montagnese, Sonja Holm-Yildiz, Nanna Scharff Poulsen, Tanya Stojkovic, Anthony Behin, Johanna Palmio, Manu Jokela, Jan L De Bleecker, Marianne de Visser, Anneke J van der Kooi, Leroy ten Dam, Cristina Domínguez González, Lorenzo Maggi, Annamaria Gallone, Anna Kostera-Pruszczyk, Anna Macias, Anna Łusakowska, Velina Nedkova, Montse Olive, Rodrigo Álvarez-Velasco, Julia Wanschitz, Carmen Paradas, Fabiola Mavillard, Giorgia Querin, Gorka Fernández-Eulate, Ros Quinlivan, Maggie C Walter, Christophe E Depuydt, Bjarne Udd, John Vissing, Benedikt Schoser, and Kristl G Claeys
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Neurology (clinical) - Abstract
Anoctamin-5 related muscle disease is caused by biallelic pathogenic variants in the anoctamin-5 gene (ANO5) and shows variable clinical phenotypes: limb-girdle muscular dystrophy type 12 (LGMD-R12), distal muscular dystrophy type 3 (MMD3), pseudometabolic myopathy or asymptomatic hyperCKaemia. In this retrospective, observational, multicentre study we gathered a large European cohort of patients with ANO5-related muscle disease to study the clinical and genetic spectrum and genotype–phenotype correlations. We included 234 patients from 212 different families, contributed by 15 centres from 11 European countries. The largest subgroup was LGMD-R12 (52.6%), followed by pseudometabolic myopathy (20.5%), asymptomatic hyperCKaemia (13.7%) and MMD3 (13.2%). In all subgroups, there was a male predominance, except for pseudometabolic myopathy. Median age at symptom onset of all patients was 33 years (range 23–45 years). The most frequent symptoms at onset were myalgia (35.3%) and exercise intolerance (34.1%), while at last clinical evaluation most frequent symptoms and signs were proximal lower limb weakness (56.9%) and atrophy (38.1%), myalgia (45.1%) and atrophy of the medial gastrocnemius muscle (38.4%). Most patients remained ambulatory (79.4%). At last evaluation, 45.9% of patients with LGMD-R12 additionally had distal weakness in the lower limbs and 48.4% of patients with MMD3 also showed proximal lower limb weakness. Age at symptom onset did not differ significantly between males and females. However, males had a higher risk of using walking aids earlier (P = 0.035). No significant association was identified between sportive versus non-sportive lifestyle before symptom onset and age at symptom onset nor any of the motor outcomes. Cardiac and respiratory involvement that would require treatment occurred very rarely. Ninety-nine different pathogenic variants were identified in ANO5 of which 25 were novel. The most frequent variants were c.191dupA (p.Asn64Lysfs*15) (57.7%) and c.2272C>T (p.Arg758Cys) (11.1%). Patients with two loss-of function variants used walking aids at a significantly earlier age (P = 0.037). Patients homozygous for the c.2272C>T variant showed a later use of walking aids compared to patients with other variants (P = 0.043). We conclude that there was no correlation of the clinical phenotype with the specific genetic variants, and that LGMD-R12 and MMD3 predominantly affect males who have a significantly worse motor outcome. Our study provides useful information for clinical follow up of the patients and for the design of clinical trials with novel therapeutic agents.
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- 2023
5. Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α
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Pedro Linares-Clemente, Fabiola Mavillard, José L Muñoz-Bravo, Ricardo Pardal, Marina Valenzuela-Villatoro, Rafael Fernández-Chacón, Leonardo Gómez-Sánchez, Jose Luis Nieto-Gonzalez, María del Carmen Gómez Rivero, Ministerio de Economía y Competitividad (España), European Commission, Junta de Andalucía, and Instituto de Salud Carlos III
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DNAJC5 ,Neurogenesis ,Biology ,Hippocampal formation ,Adult neurogenesis ,Hippocampus ,Adult-onset neuronal ceroid lipofuscinosis ,Mice ,Neural Stem Cells ,Neuronal Ceroid-Lipofuscinoses ,Neurosphere ,Animals ,Neurodegeneration ,Progenitor cell ,Mechanistic target of rapamycin ,Cells, Cultured ,PI3K/AKT/mTOR pathway ,Mice, Knockout ,Multidisciplinary ,Synaptic ,TOR Serine-Threonine Kinases ,Membrane Proteins ,synaptic neurodegeneration ,adult-onset neuronal ceroid lipofuscinosis ,HSP40 Heat-Shock Proteins ,Lysosome ,Neural stem cell ,Cell biology ,adult neurogenesis ,PNAS Plus ,lysosome ,biology.protein ,Stem cell ,Lysosomes ,Signal Transduction - Abstract
Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α). Remarkably, in CSP-α knockout mice, RGL stem cells lose quiescence postnatally and enter into a high-proliferation regime that increases the production of neural intermediate progenitor cells, thereby exhausting the hippocampal neural stem cell pool. In cell culture, stem cells in hippocampal neurospheres display alterations in proliferation for which hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is the primary cause of neurogenesis deregulation in the absence of CSP-α. In addition, RGL cells lose quiescence upon specific conditional targeting of CSP-α in adult neural stem cells. Our findings demonstrate an unanticipated cell-autonomic and circuit-independent disruption of postnatal neurogenesis in the absence of CSP-α and highlight a direct or indirect CSP-α/mTOR signaling interaction that may underlie molecular mechanisms of brain dysfunction and neurodegeneration., This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and Fondo Europeo de Desarrollo Regional (Grants BFU2013-47493-P and BFU2016-76050-P, Juan de la Cierva Contract, and Fellowships BES2008-002858 and BES2014-070405), the Junta de Andalucía (Grants P12-CTS-2232 and CTS-600), and the Instituto de Salud Carlos III.
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- 2019
6. Author response for 'Novel ANO5 intronic Roma variant alters splicing causing muscular dystrophy'
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Macarena Cabrera-Serrano, Carmen Paradas, Emilia Servián-Morilla, Eloy Rivas, and Fabiola Mavillard
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Genetics ,RNA splicing ,medicine ,Muscular dystrophy ,Biology ,medicine.disease - Published
- 2021
7. Novel ANO5 intronic Roma variant alters splicing causing muscular dystrophy
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Emilia Servián-Morilla, Eloy Rivas, Fabiola Mavillard, Macarena Cabrera-Serrano, Carmen Paradas, Junta de Andalucía, and Instituto de Salud Carlos III
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0301 basic medicine ,Roma ,RNA Splicing ,Population ,Roma population ,Anoctamins ,030105 genetics & heredity ,Biology ,ANO5 ,Muscular Dystrophies ,03 medical and health sciences ,Exon ,Genetics ,medicine ,Humans ,splice ,Muscular dystrophy ,Aberrant splicing ,education ,Genetics (clinical) ,education.field_of_study ,Alternative splicing ,Exons ,Middle Aged ,medicine.disease ,Introns ,030104 developmental biology ,RNA splicing ,Mutation (genetic algorithm) ,Mutation ,Female ,RNA Splice Sites - Abstract
The pathogenic role of intronic variants is generally difficult to assess, except for those near known splice sites for which aberrant splicing is suspected, although deeper intronic variants can also alter splicing. We have identified a novel (NM_213599.2:c.1180+6T>C) ANO5 variant that causes the exclusion of exon 12. The mutation, identified in a Roma individual, has an estimated carrier rate of 1.68% among the Iberian Roma population, this being the first ANO5 pathogenic variant communicated in this ethnic group. In this study, we have also characterized the ANO5 splice forms expressed in human muscle with the detection of an alternative transcript, in which exons 8 and 9 are spliced out., Consejería de Salud, Junta de Andalucía, Grant/Award Numbers: B-0005-2017, PIER-0100-2019, PIER-0468-2019; Instituto de Salud Carlos III, Grant/Award Numbers: PI16/00612, PI19/01497.
- Published
- 2021
8. Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy
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C. Jimenez-Mallebrera, Cristina Domínguez-González, Selena Trifunov, Jordi Díaz-Manera, Carmen Badosa, Fabiola Mavillard, Julio Montoya, Itxaso Marti, Michio Hirano, Marcos Madruga-Garrido, Carmen Paradas, Raquel Montero, Daniel Cuadras, Rafael Artuch, Ramon Martí, Jorge Alonso-Pérez, Joan Villarroya, Andres Berardo, Susana G. Kalko, Yolanda Cámara, Miguel A. Martín, Andrés Nascimento, Eduardo Ruiz-Pesini, Carlos Ortez, Cora Blázquez-Bermejo, Francesc Villarroya, Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Muscular Dystrophy Association (US), and Arturo Estopinan TK2 Research Fund
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0301 basic medicine ,Male ,Mitochondrial Diseases ,lcsh:Medicine ,Diseases ,Gastroenterology ,Mitocondris ,Basal (phylogenetics) ,0302 clinical medicine ,Medicine ,lcsh:Science ,Child ,Multidisciplinary ,Biochemical markers ,Middle Aged ,Prognosis ,Mitochondria ,Neurology ,Child, Preschool ,Marcadors bioquímics ,embryonic structures ,Biomarker (medicine) ,Female ,medicine.symptom ,After treatment ,Adult ,medicine.medical_specialty ,Growth Differentiation Factor 15 ,DNA, Mitochondrial ,Thymidine Kinase ,Article ,03 medical and health sciences ,Disease severity ,Muscular Diseases ,Internal medicine ,Genetics ,Humans ,In patient ,Myopathy ,Muscle, Skeletal ,Aged ,business.industry ,lcsh:R ,Infant ,Fibroblast Growth Factors ,030104 developmental biology ,Potential biomarkers ,lcsh:Q ,GDF15 ,business ,030217 neurology & neurosurgery ,Biomarkers ,Neuroscience - Abstract
GDF-15 is a biomarker for mitochondrial diseases. We investigated the application of GDF-15 as biomarker of disease severity and response to deoxynucleoside treatment in patients with thymidine kinase 2 (TK2) deficiency and compared it to FGF-21. GDF-15 and FGF-21 were measured in serum from 24 patients with TK2 deficiency treated 1–49 months with oral deoxynucleosides. Patients were grouped according to age at treatment and biomarkers were analyzed at baseline and various time points after treatment initiation. GDF-15 was elevated on average 30-fold in children and 6-fold in adults before the start of treatment. There was a significant correlation between basal GDF-15 and severity based on pretreatment distance walked (6MWT) and weight (BMI). During treatment, GDF-15 significantly declined, and the decrease was accompanied by relevant clinical improvements. The decline was greater in the paediatric group, which included the most severe patients and showed the greatest clinical benefit, than in the adult patients. The decline of FGF-21 was less prominent and consistent. GDF-15 is a potential biomarker of severity and of therapeutic response for patients with TK2 deficiency. In addition, we show evidence of clinical benefit of deoxynucleoside treatment, especially when treatment is initiated at an early age., This work was supported by research grants of Plan Nacional de I + D + I and Instituto de Salud Carlos III (ISCIII), Subdirección General de Evaluación y Fomento de la Investigación Sanitaria, projects PI16/01843 (CP), PI16/00579 and CP09/00011 (CJM), PI15/00431 (MAM), PI17/00109 (RA) and PI18/01574 (RM), co-funded with European Regional Development Fund (ERDF) “A way to achieve Europe”; multicentric grant funded by the ISCIII (PMP15/00025, MAM, RM, CP), Grants of the Ministerio de Ciencia, Innovación y Universidades SAF2017-85722 (FV) and SAF2017-87506-R (YC), the Muscular Dystrophy Association grant 577391 (MH), and the Arturo Estopinan TK2 Research Fund (MH).
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- 2020
9. Heterozygous CAPN3 missense variants causing autosomal-dominant calpainopathy in seven unrelated families
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Fabiola Mavillard, Aurelio Hernández-Lain, Emilia Servián-Morilla, Joshua S. Clayton, J. Esteban Perez, Leigh B. Waddell, Nigel G. Laing, Sandra T. Cooper, P. Rodrigo, Katrina Reardon, Macarena Cabrera-Serrano, Montse Olivé, Frances J. Evesson, Payam Soltanzadeh, Cristina Domínguez-González, N. Ermolova, A. Arteche‐López, M. Spencer, A. Corbett, Laura Gonzalez-Mera, C. Navas, Gianina Ravenscroft, E. Rivas-Infante, C. Paradas‐Lopez, A. Sanchez, Instituto de Salud Carlos III, European Commission, Generalitat de Catalunya, and National Health and Medical Research Council (Australia)
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Adult ,Male ,Histology ,Adolescent ,Mutation, Missense ,Missense variant ,Muscle Proteins ,Limb girdle ,Pathology and Forensic Medicine ,Young Adult ,CAPN3 ,Physiology (medical) ,Genotype ,medicine ,Missense mutation ,Humans ,Genetic Predisposition to Disease ,Muscular dystrophy ,Gluteal muscles ,LGMDD4 ,Genetics ,biology ,Calpain ,Skeletal muscle ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Middle Aged ,medicine.disease ,Calpainopathy ,LGMDR1 ,Pedigree ,medicine.anatomical_structure ,Neurology ,Muscular Dystrophies, Limb-Girdle ,biology.protein ,Female ,Neurology (clinical) ,Limb-girdle muscular dystrophy - Abstract
[Aims] Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN., [Methods] We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from seven unrelated families., [Results] The c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)] and c.1706T> C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction in calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin-binding site and are predicted to interfere with proteolytic activation., [Conclusions] We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants., This study was funded in part by Instituto de Salud Carlos III through the project PI14/00738 to M. O. (co-funded by European Regional Development Fund. ERDF, a way to build Europe). We thank CERCA Programme / Generalitat de Catalunya for institutional support NGL (APP1117510) and GR (APP1122952) are supported by the Australian National Health and Medical Research Council (NHMRC). This work is also funded by an NHMRC Project Grant (APP1080587).
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- 2020
10. Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy
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Francisco Javier Aguirre‐Rodríguez, Susana G. Kalko, Elena Martín-Hernández, Fabiola Mavillard, Michio Hirano, Javier Torres-Torronteras, Bruce Levin, Marcos Madruga-Garrido, Cecilia Jimenez-Mallebrera, Yuqi Tu, Juan P. Morealejo‐Aycinena, Yuelin Long, Karin Kleinsteuber, Ramon Martí, Itxaso Marti, Jasim Uddin, Olga Serrano, Caterina Garone, Concepcion Álvarez del Vayo, M. Alice Donati, Francina Munell, John L.P. Thompson, Carmen Paradas, Cristina Domínguez-González, Andrés Nascimento, M. Dolores Sardina, Kristen Engelstad, Dominguez-Gonzalez C., Madruga-Garrido M., Mavillard F., Garone C., Aguirre-Rodriguez F.J., Donati M.A., Kleinsteuber K., Marti I., Martin-Hernandez E., Morealejo-Aycinena J.P., Munell F., Nascimento A., Kalko S.G., Sardina M.D., Alvarez del Vayo C., Serrano O., Long Y., Tu Y., Levin B., Thompson J.L.P., Engelstad K., Uddin J., Torres-Torronteras J., Jimenez-Mallebrera C., Marti R., Paradas C., Hirano M., Instituto de Salud Carlos III, Generalitat de Catalunya, European Commission, Muscular Dystrophy Association (US), and Arturo Estopinan TK2 Research Fund
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0301 basic medicine ,Adult ,Compassionate Use Trials ,Male ,medicine.medical_specialty ,Neurology ,Side effect ,medicine.medical_treatment ,Deoxyribonucleosides ,Walk Test ,Gastroenterology ,Thymidine Kinase ,Article ,03 medical and health sciences ,0302 clinical medicine ,Muscular Diseases ,Internal medicine ,tk2, myopathy, nucleosides, therapy ,medicine ,Humans ,Myopathy ,Child ,Feeding tube ,Mechanical ventilation ,business.industry ,Discontinuation ,Diarrhea ,030104 developmental biology ,Child, Preschool ,Female ,Neurology (clinical) ,GDF15 ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
[Objective] Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies., [Methods] We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2‐deficient patients under a compassionate use program., [Results] In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe independently. In motor functional scales, improvements were observed in the 6‐minute walk test performance in 7 of 8 subjects, Egen Klassifikation in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated serum growth differentiation factor 15 levels decreased with treatment in all 7 patients tested. A side effect observed in 8 of the 16 patients was dose‐dependent diarrhea, which did not require withdrawal of treatment. Among 12 other TK2 patients treated with deoxynucleoside, 2 adults developed elevated liver enzymes that normalized following discontinuation of therapy., [Interpretation] This open‐label study indicates favorable side effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency. ANN NEUROL 2019;86:293–303, This work was supported in part by grants from the Spanish Carlos III Health Institute (PMP15/00025 for C.P., F.Ma., and R.M.; PI16/00579 and CP09/00011 for C.J.‐M.), Muscular Dystrophy Association (577391), Arturo Estopinan TK2 Research Fund, Generalitat de Catalunya PERIS program (SLT002/16/00370 for J.T‐T.), and European Regional Development Fund.
- Published
- 2019
11. Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
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Emilia Servián-Morilla, A. L. Pelayo-Negro, Macarena Cabrera-Serrano, Fabiola Mavillard, Nigel G. Laing, Abbie M. Adams, Gianina Ravenscroft, Alejandra Carvajal, M. A. Fernández-García, Sue Fletcher, Jose Luis Nieto-Gonzalez, Carmen Paradas, Reimar Junckerstorff, E. Rivas-Infante, J. M. Dyke, Phillipa J. Lamont, Instituto de Biomedicina de Sevilla (IBIS), [Servian-Morilla,E, Cabrera-Serrano,M, Mavillard,F, Paradas,C] Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain. [Servian-Morilla,E, Nieto-González,JL, Paradas,C] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Cabrera-Serrano,M, Rivas-Infante,E, Lamont,PJ, Ravenscroft,G, Laing,NG] Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, Perth, Australia. [Rivas-Infante,E] Department of Neuropathology, Hospital U. Virgen del Rocío/ Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain. [Carvajal,A] Neuromuscular Unit, Hospital Virgen de las Nieves, Granada, Spain. [Pelayo-Negro,AL] Neurology Department, University Hospital Marqués de Valdecilla (IDIVAL), Santander, Cantabria, Spain. [Junckerstorff,R, Dyke,JM] PathWest Laboratory Medicine WA, Section of Neuropathology, Royal Perth Hospital, Perth, WA, Australia. [Fletcher,S, Adams,AM] Centre for Comparative Genomics, Murdoch University, Perth, Australia. [Fletcher,S, Adams,AM] Perron Institute for Neurological and Translational Science, University of Western Australia, Nedlands, Australia. [Fernández-García,MA] Neurology Department, Health in Code S.L., A Coruña, Spain. [Nieto-González,JL] Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain., Supported in part by grants from the Health Institute Carlos III and FEDER a way to achieve Europe (PI16–01843 to CP, JR15/00042 to MC-S), the Fundación Progreso y Salud, Junta de Andalucía (PI-0085-2016 to JLN-G), and Australian National Health and Medical Research Council (NHMRC) Fellowships (APP1122952 and APP1117510 to GR and NGL)., Instituto de Salud Carlos III, European Commission, Junta de Andalucía, and National Health and Medical Research Council (Australia)
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0301 basic medicine ,Male ,Muscular dystrophies ,Diseases::Musculoskeletal Diseases::Muscular Diseases [Medical Subject Headings] ,Diseases::Musculoskeletal Diseases::Muscular Diseases::Muscular Disorders, Atrophic::Muscular Dystrophies [Medical Subject Headings] ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Pedigree [Medical Subject Headings] ,Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Physiological Processes::Musculoskeletal Development::Muscle Development [Medical Subject Headings] ,Muscle Development ,Anatomy::Cells::Stem Cells::Myoblasts [Medical Subject Headings] ,lcsh:RC346-429 ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Myoblasts ,Tripartite Motif Proteins ,0302 clinical medicine ,E3 ubiquitin -ligase ,Proliferation/differentiation ,Cell differentiation ,Myocyte ,Missense mutation ,Diferenciación celular ,Muscular dystrophy ,Cell proliferation ,Cells, Cultured ,Cellular Senescence ,Myogenesis ,Middle Aged ,E3 ubiquitin-ligase ,3. Good health ,Pedigree ,Female ,medicine.symptom ,Senescence ,Adult ,Proliferación celular ,Ubiquitin-Protein Ligases ,Autofagia ,Check Tags::Male [Medical Subject Headings] ,Biology ,Distrofias musculares ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors [Medical Subject Headings] ,Pathology and Forensic Medicine ,Frameshift mutation ,Muscle dystrophy ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Atrophy ,Muscular Diseases ,Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Ligases::Ubiquitin-Protein Ligase Complexes::Ubiquitin-Protein Ligases [Medical Subject Headings] ,medicine ,Autophagy ,Humans ,Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation [Medical Subject Headings] ,Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Autophagy [Medical Subject Headings] ,Myopathy ,lcsh:Neurology. Diseases of the nervous system ,TRIM32 ,Aged ,Research ,medicine.disease ,030104 developmental biology ,Check Tags::Female [Medical Subject Headings] ,Anatomy::Cells::Cells, Cultured [Medical Subject Headings] ,Cancer research ,Neurology (clinical) ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation., Supported in part by grants from the Health Institute Carlos III and FEDER a way to achieve Europe (PI16–01843 to CP, JR15/00042 to MC-S), the Fundación Progreso y Salud, Junta de Andalucía (PI-0085-2016 to JLN-G), and Australian National Health and Medical Research Council (NHMRC) Fellowships (APP1122952 and APP1117510 to GR and NGL).
- Published
- 2019
12. NOVEL intronic CAPN3 Roma mutation alters splicing causing RNA mediated decay
- Author
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Francisco J. Morón, Rainiero Ávila-Polo, Eloy Rivas, Emilia Servián-Morilla, Irene Marcos, Carmen Paradas, Marcos Madruga-Garrido, Fabiola Mavillard, Macarena Cabrera-Serrano, European Commission, Instituto de Salud Carlos III, and Junta de Andalucía
- Subjects
Male ,0301 basic medicine ,Roma ,Adolescent ,RNA Splicing ,RNA Stability ,Muscle Proteins ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Brief Communication ,03 medical and health sciences ,Exon ,0302 clinical medicine ,medicine ,Humans ,RC346-429 ,Child ,Genetics ,Messenger RNA ,Calpain ,business.industry ,General Neuroscience ,Intron ,RNA ,medicine.disease ,Founder Effect ,Introns ,030104 developmental biology ,Muscular Dystrophies, Limb-Girdle ,Mutation ,Mutation (genetic algorithm) ,RNA splicing ,Female ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,Brief Communications ,business ,030217 neurology & neurosurgery ,RC321-571 ,Limb-girdle muscular dystrophy ,Founder effect - Abstract
CAPN3 mutations cause a limb girdle muscular dystrophy. Functional characterization of novel mutations facilitates diagnosis of future cases. We have identified a novel (c.1992 + 2T>G) CAPN3 mutation that disrupts the donor splice site of intron 17 splicing out exon 17, with mRNA levels severely reduced or undetectable. The mutation induces a strong change in the 3D structure of the mRNA which supports no-go mRNA decay as the probable mechanism for RNA degradation. The mutation was identified in two unrelated Roma individuals showing a common ancestral origin and founder effect. This is the first Roma CAPN3 mutation to be reported., This project has been founded by ISCIII and FEDER “a way to achieve Europe”; Grant number PI16/00612(MC‐S) and PI16/01843 (CP). MC‐S was supported by ISCIII (JR15/00042) and Junta de Andalucia‐Consejeria de Salud (B‐0005‐2017).
- Published
- 2019
13. A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine
- Author
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Eloy Rivas, Juan J. Vílchez, Cristina Domínguez, Nigel G. Laing, Valérie Biancalana, Pablo Quiroga, Montse Olivé, Aurelio Hernández-Lain, Fabiola Mavillard, Macarena Cabrera-Serrano, Eduardo Khan, Luba Kalaydjieva, Nuria Muelas, Carmen Paradas, Jocelyn Laporte, Alejandra Carvajal, Jordi Díaz-Manera, Norma B. Romero, Bharti Morar, Mark M. Davis, David Comas, Rainiero Ávila, Instituto de Biomedicina de Sevilla [Sevilla, Spain] (IBIS/HUVR), Universidad de Sevilla-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitario Virgen del Rocío [Sevilla], The University of Western Australia (UWA), Health Research Institute [Madrid, Espagne], L’Hospitalet de Llobregat [Barcelona, Spain], CIBER de Enfermedades Raras (CIBERER), Hospital General Universitario Santa Lucía (Cartagena), Hospital Universitario Virgen de las Nieves [Granada, Spain] (HUVN), Universitat Autònoma de Barcelona (UAB), PathWest Laboratory Medicine, Royal Perth Hospital, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Universitat Pompeu Fabra [Barcelona] (UPF), Universidad de Sevilla / University of Sevilla-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
- Subjects
Adult ,0301 basic medicine ,medicine.medical_specialty ,Roma ,Neuromuscular disease ,Adolescent ,Population ,Mallory Bodies ,Compound heterozygosity ,Article ,Muscular Dystrophies ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Centronuclear myopathy ,Child ,education ,Prospective cohort study ,Adaptor Proteins, Signal Transducing ,Retrospective Studies ,education.field_of_study ,business.industry ,Tumor Suppressor Proteins ,Haplotype ,Nuclear Proteins ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Founder Effect ,Phenotype ,030104 developmental biology ,Scoliosis ,Spain ,Mutation ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Myopathies, Structural, Congenital ,Founder effect - Abstract
ObjectiveTo describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified.MethodsPatients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed.ResultsEighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma.ConclusionWe have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.
- Published
- 2018
14. Proteolytic Processing of Neurexins by Presenilins Sustains Synaptic Vesicle Release
- Author
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Rafael J. Camacho-Garcia, Juan A. Paez-Gomez, Fabiola Mavillard, Emilia Servián-Morilla, Estefanía Robles-Lanuza, Francisco G. Scholl, Amalia Martinez-Mir, Ana C. Sanchez-Hidalgo, and Carlos A. Saura
- Subjects
0301 basic medicine ,Male ,Neurotransmission ,Synaptic vesicle ,Synaptic Transmission ,neuroligins ,Synapse ,03 medical and health sciences ,Glutamatergic ,chemistry.chemical_compound ,Mice ,synapse ,Postsynaptic potential ,Calcium flux ,Animals ,Neurotransmitter ,Neural Cell Adhesion Molecules ,Research Articles ,neurexins ,General Neuroscience ,synaptic adhesion ,Presenilins ,Alzheimer's disease ,Cell biology ,Rats ,030104 developmental biology ,chemistry ,Proteolysis ,Excitatory postsynaptic potential ,Female ,Synaptic Vesicles - Abstract
Proteolytic processing of synaptic adhesion components can accommodate the function of synapses to activity-dependent changes. The adhesion system formed by neurexins (Nrxns) and neuroligins (Nlgns) bidirectionally orchestrate the function of presynaptic and postsynaptic terminals. Previous studies have shown that presenilins (PS), components of the gamma-secretase complex frequently mutated in familial Alzheimer's disease, clear from glutamatergic terminals the accumulation of Nrxn C-terminal fragments (Nrxn-CTF) generated by ectodomain shedding. Here, we characterized the synaptic consequences of the proteolytic processing of Nrxns in cultured hippocampal neurons from mice and rats of both sexes. We show that activation of presynaptic Nrxns with postsynaptic Nlgn1 or inhibition of ectodomain shedding in axonal Nrxn1-β increases presynaptic release at individual terminals, likely reflecting an increase in the number of functional release sites. Importantly, inactivation of PS inhibits presynaptic release downstream of Nrxn activation, leaving synaptic vesicle recruitment unaltered. Glutamate-receptor signaling initiates the activity-dependent generation of Nrxn-CTF, which accumulate at presynaptic terminals lacking PS function. The sole expression of Nrxn-CTF decreases presynaptic release and calcium flux, recapitulating the deficits due to loss of PS function. Our data indicate that inhibition of Nrxn processing by PS is deleterious to glutamatergic function.SIGNIFICANCE STATEMENTTo gain insight into the role of presenilins (PS) in excitatory synaptic function, we address the relevance of the proteolytic processing of presynaptic neurexins (Nrxns) in glutamatergic differentiation. Using synaptic fluorescence probes in cultured hippocampal neurons, we report that trans-synaptic activation of Nrxns produces a robust increase in presynaptic calcium levels and neurotransmitter release at individual glutamatergic terminals by a mechanism that depends on normal PS activity. Abnormal accumulation of Nrxn C-terminal fragments resulting from impaired PS activity inhibits presynaptic calcium signal and neurotransmitter release, assigning synaptic defects to Nrxns as a specific PS substrate. These data may provide links into how loss of PS activity inhibits glutamatergic synaptic function in Alzheimer's disease patients.
- Published
- 2017
15. A Poglut1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss
- Author
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Carmen Paradas, Anne Bigot, Beatriz Estrada, Yolanda Morgado, Rafael Fernández-Chacón, Hideyuki Takeuchi, Tom V. Lee, Estela Area-Gomez, Leonardo Gómez-Sánchez, Eloy Rivas, Eduard Gallardo, José A. Martínez-López, Michio Hirano, Macarena Cabrera-Serrano, Maria Rivero, Robert S. Haltiwanger, Xavier Suárez-Calvet, C. Márquez, Emilia Servián-Morilla, Jordi Clarimón, Guillermo Pita, Hamed Jafar-Nejad, Fabiola Mavillard, Jose Luis Nieto-Gonzalez, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, and Universidad de Sevilla. CTS-600
- Subjects
0301 basic medicine ,muscular dystrophy ,satellite cell ,Glycosylation ,Notch ,Satellite Cells, Skeletal Muscle ,Biopsy ,Notch signaling pathway ,Poglut1 ,Biology ,Muscular Dystrophies ,03 medical and health sciences ,O -glycosylation ,medicine ,Myocyte ,Missense mutation ,Humans ,Muscular dystrophy ,Musculoskeletal System ,Research Articles ,Genetics ,O-glycosylation ,Receptors, Notch ,Myogenesis ,Muscles ,Skeletal muscle ,Glycosyltransferases ,Sequence Analysis, DNA ,medicine.disease ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Glucosyltransferases ,Spain ,satellitecell ,Mutation ,Molecular Medicine ,O‐glycosylation ,POGLUT1 ,PAX7 ,ITGA7 ,Development & Differentiation ,Satellite cell ,Research Article ,Signal Transduction - Abstract
Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limbgirdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and in vivo experiments demonstrated that the mutation reduces Oglucosyltransferase activity on Notch and impairs muscle development. Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific adystroglycan hypoglycosylation not present in patients’ fibroblasts. Primary myoblasts from patients showed slow proliferation, facilitated differentiation, and a decreased pool of quiescent PAX7+ cells. A robust rescue of the myogenesis was demonstrated by increasing Notch signaling. None of these alterations were found in muscles from secondary dystroglycanopathy patients. These data suggest that a key pathomechanism for this novel form of muscular dystrophy is Notch-dependent loss of satellite cells. Junta de Andalucía PI-0017-2014
- Published
- 2016
16. BIN1 founder mutation in the Spanish gypsy population is the most frequent cause of adult onset centronuclear myopathies in the south of Spain
- Author
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Carmen Paradas, Nuria Muelas, Jocelyn Laporte, Nigel G. Laing, A. Carvajal, Macarena Cabrera-Serrano, E. Verges, Juan J. Vílchez, Fabiola Mavillard, E. Rivas-Infante, R. Avila, David Comas, Norma B. Romero, J. Diaz, Bharti Morar, Montse Olivé, and Luba Kalaydjieva
- Subjects
Genetics ,education.field_of_study ,Neurology ,Pediatrics, Perinatology and Child Health ,Population ,Neurology (clinical) ,Biology ,education ,Founder mutation ,Genetics (clinical) - Published
- 2017
17. The phenotype of POGLUT1 mutations: Broad clinical expression and distinctive muscle imaging pattern
- Author
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Carmen Paradas, Juan J. Vílchez, G. Cantero, Emilia Servián-Morilla, E. Rivas-Infante, Hideyuki Takeuchi, Fabiola Mavillard, Nuria Muelas, and Macarena Cabrera-Serrano
- Subjects
Neurology ,Expression (architecture) ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Biology ,Phenotype ,Genetics (clinical) ,Cell biology - Published
- 2017
18. PKA-Mediated Golgi Remodeling During cAMP Signal Transmission
- Author
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J. Hidalgo, Kostantin L. Levitsky, Angel Velasco, Fabiola Mavillard, and Diego Megías
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Golgi Apparatus ,Biology ,Ligands ,Biochemistry ,Cell Line ,symbols.namesake ,Structural Biology ,Catalytic Domain ,Cyclic AMP ,Fluorescence Resonance Energy Transfer ,Genetics ,Extracellular ,Humans ,Protein kinase A ,Molecular Biology ,Cell Nucleus ,Colocalization ,Cell Biology ,Golgi apparatus ,Cyclic AMP-Dependent Protein Kinases ,Transport protein ,Cell biology ,Microscopy, Electron ,Protein Transport ,Cytosol ,Microscopy, Fluorescence ,Cytoplasm ,symbols ,Signal transduction ,Signal Transduction - Abstract
Cyclic AMP (cAMP)-dependent protein kinase A (PKA) is part of the set of signaling proteins that are stably associated to the cytosolic surface of Golgi membranes in mammalian cells. In principle, Golgi-associated PKA could participate in either signal transduction events and/or the coordination of Golgi transport activities. Here, we show data indicating that although Golgi-associated PKA is activated fast and efficiently during cell stimulation by an extracellular ligand it does not contribute significantly to cAMP signal transmission to the nucleus. Instead, most of the PKA catalytic subunits Calphaderived from the Golgi complex remain localized in the perinuclear cytoplasm where they induce changes in Golgi structural organization. Thus, in stimulated cells the Golgi complex appears collapsed, showing increased colocalization of previously segregated markers and exhibiting merging of different proximal cisternae within a single stack. In contrast, the trans-Golgi network remains as a separate compartment. Consequently, the rate of protein transport is increased whereas glycan processing is not severely affected. This remodeling process requires the presence of PKA activity associated to the Golgi membranes. Together these data indicate that Golgi-associated PKA activity is involved in the adaptation of Golgi dynamic organization to extracellular signaling events.
- Published
- 2009
19. A POGLUT1 mutation causes a muscular dystrophy with reduced notch signaling and satellite cell loss
- Author
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Rafael Fernández-Chacón, Anne Bigot, G. Cantero-Nieto, Emilia Servián-Morilla, Jordi Clarimón, Robert S. Haltiwanger, Hideyuki Takeuchi, Carmen Paradas, Fabiola Mavillard, and Hamed Jafar-Nejad
- Subjects
biology ,Notch signaling pathway ,medicine.disease ,biology.organism_classification ,Cell loss ,Cell biology ,Neurology ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,medicine ,Satellite (biology) ,Neurology (clinical) ,Muscular dystrophy ,Genetics (clinical) - Published
- 2016
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