41 results on '"Gallano, Pia"'
Search Results
2. Distal myopathy due to digenic inheritance of TIA1 and SQSTM1 variants in two unrelated Spanish patients
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Bermejo-Guerrero, Laura, de Fuenmayor Fernández-de la Hoz, Carlos Pablo, González-Quereda, Lidia, Segarra-Casas, Alba, Nedkova, Velina, Gallano, Pia, Martín-Jiménez, Paloma, Hernández-Laín, Aurelio, Olivé, Montse, Arteche-López, Ana, and Domínguez-González, Cristina
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- 2023
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3. A novel phenotype of AChR-deficiency syndrome with predominant facial and distal weakness resulting from the inclusion of an evolutionary alternatively-spliced exon in CHRNA1
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Rodríguez Cruz, Pedro M, Ravenscroft, Gianina, Natera, Daniel, Carr, Aisling, Manzur, Adnan, Liu, Wei Wei, Vella, Norbert R, Jericó, Ivonne, Gonzalez-Quereda, Lidia, Gallano, Pia, Montalto, Simon Attard, Davis, Mark R, Lamont, Phillipa J, Laing, Nigel G, Bourque, Pierre, Nascimento, Andres, Muntoni, Francesco, Polavarapu, Kiran, Lochmüller, Hanns, Palace, Jacqueline, and Beeson, David
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- 2023
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4. Anoctamin 5 (ANO5) muscular dystrophy—three different phenotypes and a new histological pattern
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Seguí, Ferran, Gonzalez-Quereda, Lidia, Sanchez, Aurora, Matas-García, Ana, Garrabou, Gloria, Rodriguez, Maria José, Gallano, Pia, Grau, Josep Maria, and Milisenda, José César
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- 2020
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5. Utility of two SMN1 variants to improve spinal muscular atrophy carrier diagnosis and genetic counselling
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Alías, Laura, Bernal, Sara, Calucho, Maite, Martínez, Elisabeth, March, Francesca, Gallano, Pia, Fuentes-Prior, Pablo, Abuli, Anna, Serra-Juhe, Clara, and Tizzano, Eduardo F.
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- 2018
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6. Publisher Correction: Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein
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Milev, Miroslav P., Stanga, Daniela, Schänzer, Anne, Nascimento, Andrés, Saint-Dic, Djenann, Ortez, Carlos, Natera-de Benito, Daniel, Barrios, Desiré González, Colomer, Jaume, Badosa, Carmen, Jou, Cristina, Gallano, Pia, Gonzalez-Quereda, Lidia, Töpf, Ana, Johnson, Katherine, Straub, Volker, Hahn, Andreas, Sacher, Michael, and Jimenez-Mallebrera, Cecilia
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- 2020
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7. Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein
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Milev, Miroslav P., Stanga, Daniela, Schänzer, Anne, Nascimento, Andrés, Saint-Dic, Djenann, Ortez, Carlos, Natera-de Benito, Daniel, Barrios, Desiré González, Colomer, Jaume, Badosa, Carmen, Jou, Cristina, Gallano, Pia, Gonzalez-Quereda, Lidia, Töpf, Ana, Johnson, Katherine, Straub, Volker, Hahn, Andreas, Sacher, Michael, and Jimenez-Mallebrera, Cecilia
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- 2019
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8. Muscle imaging in muscle dystrophies produced by mutations in the EMD and LMNA genes
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Díaz-Manera, Jordi, Alejaldre, Aida, González, Laura, Olivé, Montse, Gómez-Andrés, David, Muelas, Nuria, Vílchez, Juan José, Llauger, Jaume, Carbonell, Pilar, Márquez-Infante, Celedonio, Fernández-Torrón, Roberto, Poza, Juan José, López de Munáin, Adolfo, González-Quereda, Lidia, Mirabet, Sonia, Clarimon, Jordi, Gallano, Pía, Rojas-García, Ricard, Gallardo, Eduard, and Illa, Isabel
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- 2016
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9. Genetic diagnosis of Duchenne and Becker muscular dystrophy through mRNA analysis: new splicing events.
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Segarra-Casas, Alba, Domínguez-González, Cristina, Hernández-Laín, Aurelio, Sanchez-Calvin, Maria Teresa, Camacho, Ana, Rivas, Eloy, Campo-Barasoain, Andrea, Madruga, Marcos, Ortez, Carlos, Natera-de Benito, Daniel, Nascimento, Andrés, Codina, Anna, Rodriguez, Maria Jose, Gallano, Pia, and Gonzalez-Quereda, Lidia
- Abstract
Background: Up to 7% of patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) remain genetically undiagnosed after routine genetic testing. These patients are thought to carry deep intronic variants, structural variants or splicing alterations not detected through multiplex ligation-dependent probe amplification or exome sequencing. Methods: RNA was extracted from seven muscle biopsy samples of patients with genetically undiagnosed DMD/BMD after routine genetic diagnosis. RT-PCR of the DMD gene was performed to detect the presence of alternative transcripts. Droplet digital PCR and whole-genome sequencing were also performed in some patients. Results: We identified an alteration in the mRNA level in all the patients. We detected three pseudoexons in DMD caused by deep intronic variants, two of them not previously reported. We also identified a chromosomal rearrangement between Xp21.2 and 8p22. Furthermore, we detected three exon skipping events with unclear pathogenicity. Conclusion: These findings indicate that mRNA analysis of the DMD gene is a valuable tool to reach a precise genetic diagnosis in patients with a clinical and anatomopathological suspicion of dystrophinopathy that remain genetically undiagnosed after routine genetic testing. [ABSTRACT FROM AUTHOR]
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- 2023
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10. CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative
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Luque, Juan M., Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis A., Montoliu, Lluís, Carracedo, Angel, Millán, José M., Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa María, Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José Antonio, Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero-López, Rosa, Jiménez-Estrada, Juan Andrés, Manguan-García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona Abellón, Rosario, Rivera-Barahona, Ana, Rodríguez de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno-Estellés, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., Nieto, M. Ángela, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto, Sanz, Pascual, Rubio, Vicente, and Llácer, José L.
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Biomedical Research ,Epidemiology ,Novel genes ,Research network ,New therapeutic approaches ,Rare diseases ,Rare Diseases ,Diagnòstic ,Diagnosis ,Genetics ,Humans ,Malalties rares ,Epidemiologia ,Genètica ,Genetics (clinical) - Abstract
13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix A, CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research., This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and Innovation
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- 2022
11. Phenotypic variability in a Spanish family with a Caveolin-3 mutation
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González-Pérez, Paloma, Gallano, Pía, González-Quereda, Lidia, Rivas-Infante, Eloy, Teijeira, Susana, Navarro, Carmen, and Bautista-Lorite, Juan
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- 2009
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12. A new homozygous missense variant in LMOD3 gene causing mild nemaline myopathy with prominent facial weakness
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Segarra-Casas, Alba, Collet, Roger, Gonzalez-Quereda, Lidia, Vesperinas, Ana, Caballero-Ávila, Marta, Carbayo, Alvaro, Díaz-Manera, Jordi, Rodriguez, María José, Gallardo, Eduard, Gallano, Pia, and Olivé, Montse
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- 2023
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13. Evidence-Based Consensus and Systematic Review on Reducing the Time to Diagnosis of Duchenne Muscular Dystrophy
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Aartsma-Rus, Annemieke, Hegde, Madhuri, Ben-Omran, Tawfeg, Buccella, Filippo, Ferlini, Alessandra, Gallano, Pia, Howell, R. Rodney, Leturcq, France, Martin, Ann S., Potulska-Chromik, Anna, Saute, Jonas A., Schmidt, Wolfgang M., Sejersen, Thomas, Tuffery-Giraud, Sylvie, Uyguner, Zehra Oya, Witcomb, Luci A., Yau, Shu, and Nelson, Stanley F.
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- 2019
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14. Identification of a Novel Founder Mutation in the DYSF Gene Causing Clinical Variability in the Spanish Population
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Vilchez, Juan J., Gallano, Pia, Gallardo, Eduard, Lasa, Adriana, Rojas-García, Ricardo, Freixas, Alba, De Luna, Noemí, Calafell, Francesc, Sevilla, Teresa, Mayordomo, Fernando, Baiget, Montserrat, and Illa, Isabel
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- 2005
15. Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
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Juan-Mateu Jonàs, Rodríguez Maria, Nascimento Andrés, Jiménez-Mallebrera Cecilia, González-Quereda Lidia, Rivas Eloy, Paradas Carmen, Madruga Marcos, Sánchez-Ayaso Pedro, Jou Cristina, González-Mera Laura, Munell Francina, Roig-Quilis Manuel, Rabasa Maria, Hernández-Lain Aurelio, Díaz-Manera Jorge, Gallardo Eduard, Pascual Jordi, Verdura Edgard, Colomer Jaume, Baiget Montserrat, Olivé Montse, and Gallano Pia
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Dystrophin ,DMD ,Symptomatic carrier ,Duchenne muscular dystrophy ,Becker muscular dystrophy ,X-chromosome inactivation ,Medicine - Abstract
Abstract Background Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy. Methods We reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females. Results Symptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found. Conclusions Skewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene.
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- 2012
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16. Novel PLEKHG5 mutations in a patient with childhood‐onset lower motor neuron disease.
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Gonzalez‐Quereda, Lidia, Pagola, Inmaculada, Fuentes Prior, Pablo, Bernal, Sara, Rodriguez, Maria Jose, Torné, Laura, Salgado Garrido, Josefa, Gallano, Pia, and Jericó, Ivonne
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MOTOR neuron diseases ,NF-kappa B ,SPINAL muscular atrophy - Abstract
The PLEKHG5 gene encodes a protein that activates the nuclear factor kappa B (NFκB) signaling pathway. Mutations in this gene have been associated with distal spinal muscular atrophy IV and intermediate axonal neuropathy C, both with an autosomal recessive mode of inheritance. Two families with low motor neuron disease (LMND) caused by mutations in PLEKHG5 have been reported to date. We present a third LMND family, the first nonconsanguineous, due to two not previously reported PLEKHG5 mutations. Our results confirm and extend previous findings linking PLEKHG5 mutations to lower motor neuron diseases. [ABSTRACT FROM AUTHOR]
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- 2021
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17. New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.
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Alonso-Pérez, Jorge, González-Quereda, Lidia, Bello, Luca, Guglieri, Michela, Straub, Volker, Gallano, Pia, Semplicini, Claudio, Pegoraro, Elena, Zangaro, Vittoria, Nascimento, Andrés, Ortez, Carlos, Comi, Giacomo Pietro, Dam, Leroy ten, Visser, Marianne De, Kooi, A J van der, Garrido, Cristina, Santos, Manuela, Schara, Ulrike, Gangfuß, Andrea, and Løkken, Nicoline
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LIMB-girdle muscular dystrophy ,FACIOSCAPULOHUMERAL muscular dystrophy ,PROTEIN expression ,MUSCULAR dystrophy diagnosis ,MUSCULAR dystrophy ,RESEARCH ,RESEARCH methodology ,RETROSPECTIVE studies ,EVALUATION research ,MEDICAL cooperation ,COMPARATIVE studies ,GENETIC techniques ,LONGITUDINAL method - Abstract
Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies. [ABSTRACT FROM AUTHOR]
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- 2020
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18. Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.
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Bogliolo, Massimo, Pujol, Roser, Aza-Carmona, Miriam, Muñoz-S ubirana, Núria, Rodriguez-Santiago, Benjamin, Antonio Casado, José, Rio, Paula, Bauser, Christopher, Reina-Castillón, Judith, Lopez-Sanchez, Marcos, Gonzalez-Quereda, Lidia, Gallano, Pia, Catalá, Albert, Ruiz-Llobet, Ana, Badell, Isabel, Diaz-Heredia, Cristina, Hladun, Raquel, Senent, Leonort, Argiles, Bienvenida, and Bergua Burgues, Juan Miguel
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Purpose Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies. Methods 68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test FANCA missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies. Results We identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two FANCA variants reported in mutations databases as 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) Conclusion WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source. [ABSTRACT FROM AUTHOR]
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- 2020
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19. The proα2 (V) collagen gene (COL5A2) maps to 2q14→2q32, syntenic to the proα1 (III) collagen locus (COL3A1)
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Huerre-Jeanpierre, Cécile, Henry, Isabelle, Bernard, M., Gallano, Pia, Weil, Dominique, Grzeschik, K. H., Ramirez, F., and Junien, Claudine
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- 1986
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20. The organization of two related subfamilies of a human tandemly repeated DNA is chromosome specific
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Jeanpierre, M., Weil, Dominique, Gallano, Pia, Creau-Goldberg, Nicole, and Junien, Claudine
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- 1985
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21. LGMD2I in Spanish and Croatian Populations
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Freixas, Alba, Olive, Montserrat, Canki-Klain, Nina, Povedano, Monica, Jauma, S, Colomer, Jaume, Rodriguez, Maria Jose, Martinez Matos, JA, Baiget, Montserrat, and Gallano, Pia
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LGMD 2I ,FKRP - Abstract
Limb Girdle Muscular Dystrophy type 2I (LGMD2I) is an autosomal recessive muscular dystrophy caused by mutations in the Fukutin Related Protein (FKRP). This gene is located at 19q13.3 and contains four exons. Immunohistochemical analysis is not possible to date because no specific antibodies have been isolated. Thus, mutational analysis is the method to obtain an accurate molecular diagnosis of the disease. The aim of this work is: (1) to diagnose the patients with clinical features suggesting LGMD2I, (2) to observe the frequency of this pathology in these two populations and, (3) to offer genetic counselling to the affected families. We studied 80 Spanish and Croatian patients presenting a LGMD2I phenotype and in whom we previously excluded a dystrophinopathy, a LGMD2A, a LGMD2C and a LGMD2D. The molecular study was performed following two different techniques. First of all, we analyzed the presence of the L276I mutation (reccurrent in North European population) by restriction enzyme analysis. Moreover, we sequenced the exon 4 (unique coding exon of FKRP gene). We found four missense mutations in eleven patients: E55Q, R143S, L276I and G373S. Two of these mutations (E55Q and G373S) has not been previously described. Their pathogenia was demonstrated by the analysis of 50 chromosomes from normal controls and 50 chromosomes from other myopathy patients (sarcoglycanopathies, DMD, BMD, myotonic dystrophy, caveolinopathy). The L276I mutation was identified in eight patients (3 Spanish and 5 Croatian) and should be considered the more frequent FKRP mutation in the populations studied. The low number of FKRP mutations identified despite the patients were very well classified could indicate the low frequency of LGMD2I in these two populations.
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- 2006
22. Limb girdle muscular dystrophy 2I in Spanish and Croatian population
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Freixas , A, Canki-Klain, Nina, Olive, M, Rodriguez, M, Calaf, M, Colomer, J, Arteaga, R, Baiget, M, and Gallano, Pia
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Limb Girdle muscular dystrophy ,autosomal recessive ,LGMD2I ,fukutin related protein ,FKRP ,mutations ,Spain ,Croatia - Abstract
Limb Girdle Muscular Dystrophy type 2I (LGMD2I) is an autosomal recessive muscular dystrophy caused by mutations in the Fukutin Related Protein(FKRP). This gene is located at 19q13.3 and contains four exons. Immunohistochemical analysis is not possible to date because no specific antibodies have been isolated. Thus, mutational analysis is the method to obtain an accurate molecular diagnosis of the disease. The aim of this work is: 1) to diagnose the patients with clinical features suggesting LGMD2I, 2) to observe the frequency of this pathology in these two populations and, 3) to offer genetic counselling to the affected families. We studied 60 Spanish and 10 Croatian patients presenting a LGMD2I phenotype and in whom we previously excluded a dystrophinopathy, LGMD2A, LGMD2C and LGMD2D. The molecular study was performed following two steps: 1) The analysis of the L276L mutation reccurrent in North European population) by restriction enzyme analysis. 2)The sequencing of the unique coding exon 4. We found four missens mutations in seven patients: E55Q, R143S, L276L and G373S, two of them were novel mutations: E55Q and g373S. Their pathogenia were demonstrate analysing 50 chromosomes from normal controls and 50 chromosomes from other myopathy patients. The L276L mutation was identified in four patients (3Spanish and 1 Croatian) and should be considered the more frequent FKRP mutation in the population studied. The low number of FKRP mutations identified despite the patients were very well classified could indicate the low frequency of LGMD2I in these two populations.
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- 2006
23. Dysferlinopathy masquerading as a refractory polymyositis
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Loureiro Amigo, Jose, Gallardo, Eduard, Gallano, Pia, and Grau-Junyent, Josep M.
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- 2015
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24. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations.
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Juan-Mateu, Jonas, Gonzalez-Quereda, Lidia, Rodriguez, Maria Jose, Baena, Manel, Verdura, Edgard, Nascimento, Andres, Ortez, Carlos, Baiget, Montserrat, and Gallano, Pia
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GENETIC mutation ,PHENOTYPES ,DUCHENNE muscular dystrophy ,NUCLEOTIDE sequence ,COMPUTER algorithms - Abstract
Recent advances in molecular therapies for Duchenne muscular dystrophy (DMD) require precise genetic diagnosis because most therapeutic strategies are mutation-specific. To understand more about the genotype-phenotype correlations of the DMD gene we performed a comprehensive analysis of the DMD mutational spectrum in a large series of families. Here we provide the clinical, pathological and genetic features of 576 dystrophinopathy patients. DMD gene analysis was performed using the MLPA technique and whole gene sequencing in blood DNA and muscle cDNA. The impact of the DNA variants on mRNA splicing and protein functionality was evaluated by in silico analysis using computational algorithms. DMD mutations were detected in 576 unrelated dystrophinopathy families by combining the analysis of exonic copies and the analysis of small mutations. We found that 471 of these mutations were large intragenic rearrangements. Of these, 406 (70.5%) were exonic deletions, 64 (11.1%) were exonic duplications, and one was a deletion/duplication complex rearrangement (0.2%). Small mutations were identified in 105 cases (18.2%), most being nonsense/frameshift types (75.2%). Mutations in splice sites, however, were relatively frequent (20%). In total, 276 mutations were identified, 85 of which have not been previously described. The diagnostic algorithm used proved to be accurate for the molecular diagnosis of dystrophinopathies. The reading frame rule was fulfilled in 90.4% of DMD patients and in 82.4% of Becker muscular dystrophy patients (BMD), with significant differences between the mutation types. We found that 58% of DMD patients would be included in single exon-exon skipping trials, 63% from strategies directed against multiexon-skipping exons 45 to 55, and 14% from PTC therapy. A detailed analysis of missense mutations provided valuable information about their impact on the protein structure. [ABSTRACT FROM AUTHOR]
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- 2015
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25. Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes.
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Juan-Mateu, Jonàs, González-Quereda, Lidia, Rodríguez, Maria José, Verdura, Edgard, Lázaro, Kira, Jou, Cristina, Nascimento, Andrés, Jiménez-Mallebrera, Cecilia, Colomer, Jaume, Monges, Soledad, Lubieniecki, Fabiana, Foncuberta, Maria Eugenia, Pascual-Pascual, Samuel Ignacio, Molano, Jesús, Baiget, Montserrat, and Gallano, Pia
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DUCHENNE muscular dystrophy ,GENETIC mutation ,RNA splicing ,PHENOTYPES ,CELLULAR signal transduction ,EXONS (Genetics) ,BIOCHEMISTRY ,MOLECULAR biology - Abstract
DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements. [ABSTRACT FROM AUTHOR]
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- 2013
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26. Distal anterior compartment myopathy: A dysferlin mutation causing a new muscular dystrophy phenotype.
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Illa, Isabel, Serrano-Munuera, Carme, Gallardo, Eduard, Lasa, Adriana, Rojas-García, Ricardo, Palmer, Jaume, Gallano, Pia, Baiget, Montserrat, Matsuda, Chie, and Brown, Robert H.
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- 2001
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27. Severe limb girdle muscular dystrophy in Spanish gypsies: further evidence for a founder mutation in the γ-sarcoglycan gene.
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Lasa, Adriana, Piccolo, Federica, de Diego, Carles, Jeanpierre, Marc, Colomer, Jaume, Rodríguez, Maria José, Urtizberea, Jon Andoni, Baiget, Montserrat, Kaplan, Jean Claude, and Gallano, Pia
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MUSCULAR dystrophy genetics ,ROMANIES - Abstract
Limb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive muscular dystrophy with primary γ-sarcoglycan deficiency, generally associated with a severe clinical course. γ-sarcoglycan, a 35 kDa dystrophin-associated protein, is encoded by a single gene on chromosome 13q12. Six different mutations have been described in that gene, and it has been proved they are the origin of the disease. One of these mutations (C283Y), a G → A transition in codon 283, was recently and exclusively identified in Gypsy patients from different European countries. We report the study of 11 LGMD2C unrelated Gypsy families (nine Spanish and two Portugese). The muscle biopsies of these patients showed a drastically decreased immunostaining with α and γ-sarcoglycan antibodies. All the patients were homozygous for C283Y missense mutation, and all affected chromosomes (patients and heterozygous relatives) carried the allele 5 (112 bp) of the intragenic microsatellite D13S232. Unexpectedly, this allele is most frequent in the Caucasian population but not in the normal Gypsy population. The clinical severity of all patients demonstrates that the C283Y missense mutation in a homozygous state causes a severe LGMD2C (DMD-like). The elevated number of families ascertained let us assume that LGMD2C is prevalent in the Gypsy population, and that all the families have inherited a founding mutation. [ABSTRACT FROM AUTHOR]
- Published
- 1998
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28. Lambda lg constant region genes are translocated to chromosome 8 in Burkitt's lymphoma with t(8:22.
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Chapelte, Albert de la, Lenoir, Gilbert, Bouè, Joëlle, Bouè, Andre, Gallano, Pia, Huerre, Cècile, Szajnert, Marie-France, Jeanpierre, Marc, LaloueP, Jean-Marc, and Kaplan, Jean-Claude
- Published
- 1983
29. A novel insertional mutation of a single base in exon 12 of the dystrophin gene.
- Author
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Lasa, Adriana, Gallano, Pia, Colomer, Jaume, and Baiget, Montserrat
- Published
- 1995
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30. Three novel point mutations in the dystrophin gene in DMD patients.
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Lasa, Adriana, Gallano, Pia, and Baiget, Montserrat
- Published
- 1997
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31. The Phenotype and Genotype of Congenital Myopathies Based on a Large Pediatric Cohort.
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Natera-de Benito, Daniel, Ortez, Carlos, Jou, Cristina, Jimenez-Mallebrera, Cecilia, Codina, Anna, Carrera-García, Laura, Expósito-Escudero, Jessica, Cesar, Sergi, Martorell, Loreto, Gallano, Pia, Gonzalez-Quereda, Lidia, Cuadras, Daniel, Colomer, Jaume, Yubero, Delia, Palau, Francesc, and Nascimento, Andres
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- *
PHENOTYPES , *MUSCLE diseases , *NEMALINE myopathy , *GENOTYPES , *MOLECULAR diagnosis , *INTELLECTUAL disabilities - Abstract
Background: Congenital myopathies (CMs) are a clinically and genetically heterogeneous group of hereditary muscular disorders. The distribution of genetic and histologic subtypes has been addressed in only a few cohorts, and the relationship between phenotypes and genotypes is only partially understood.Methods: This is a retrospective cross-sectional data collection study conducted at a single center. The clinical, histopathological, and molecular characterization of 104 patients with CM is reported.Results: The most common histopathological subtype was core myopathy (42%). Patients with severe endomysial fibrosis were more commonly unable to walk than patients with only a mild-grade endomysial fibrosis (56% vs 16%). Inability to walk was also more prevalent in patients with severe fatty replacement (44% vs 19%). The genetic etiology was more frequently identified among those patients with "specific" histologic findings (74% vs 62%). A definite molecular diagnosis was reached in 65 of 104 patients (62%), with RYR1 (24/104) and TTN (8/104) being the most frequent causative genes. Neonatal onset occurred in 56%. Independent ambulation was achieved by 74%. Patients who walked late were more likely to become wheelchair-dependent. Respiratory support was needed in one of three patients. Gastrostomy placement was required in 15%. Cardiac involvement was observed in 3%, scoliosis in 43%, and intellectual disability in 6%.Conclusions: This study provides an updated picture of the clinical, histopathological, and molecular landscape of CMs. Independently of the causative gene, fibrosis and fatty replacement in muscle biopsy specimens are associated with clinical severity. Mutations in TTN are responsible for a higher proportion of cases than previously thought. [ABSTRACT FROM AUTHOR]- Published
- 2021
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32. Early and long-term effect of the treatment with pyridostigmine in patients with GMPPB-related congenital myasthenic syndrome.
- Author
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Bobadilla-Quesada, Edna Julieth, Natera-de Benito, Daniel, Carrera-García, Laura, Ortez, Carlos, Exposito-Escudero, Jessica, Jimenez-Mallebrera, Cecilia, Jou, Cristina, Codina, Anna, Corbera, Joan, Moya, Obdulia, Saez, Veronica, Gonzalez-Quereda, Lidia, Gallano, Pia, Colomer, Jaume, Cuadras, Daniel, Medina, Julita, Yoldi, María Eugenia, and Nascimento, Andrés
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- *
CONGENITAL myasthenic syndromes , *TREATMENT effectiveness , *MUSCULAR dystrophy , *FACIOSCAPULOHUMERAL muscular dystrophy , *AGE factors in disease , *FUNCTIONAL assessment - Abstract
• Patients with GMPPB-CMS responded dramatically to pyridostigmine in a few hours. • A moderate decrease in motor function was found after being treated during one year. • Nonetheless, motor function was still significantly better than before treatment. • Early treatment may have long-term effects such as preventing scoliosis development. GMPPB mutations cause congenital myasthenic syndromes (CMS) overlapping with muscular dystrophy. Treatment with pyridostigmine has been reported to be effective in those patients. Nevertheless, results of functional motor assessments to determine its precise impact on the short and long term were not available. We describe the response to treatment with pyridostigmine in three siblings with GMPPB -related CMS using functional motor scales performed regularly over a period of 40 months. The beneficial effect of the treatment was outstanding within the first hours, with all the scales showing a dramatic increase in only two days. This remarkable improvement remained steady during 12 months but a moderate decrease was subsequently detected in two of the three patients. Despite this decline in the scores of the scales at the end of follow up, the functional motor status of the patients was still significantly better than it was before starting treatment. The introduction of pyridostigmine at an early age of the disease in one of the patients, before the onset of scoliosis, may have had a protective effect on it. [ABSTRACT FROM AUTHOR]
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- 2020
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33. Cylindrical spirals in two families: Clinical and genetic investigations.
- Author
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Beecroft, Sarah J, Olive, Montse, Quereda, Lidia Gonzalez, Gallano, Pia, Ojanguren, Isabel, McLean, Catriona, McCombe, Pamela, Laing, Nigel G, and Ravenscroft, Gianina
- Subjects
- *
INVESTIGATIONS , *SARCOPLASMIC reticulum , *PATHOLOGY , *NEMALINE myopathy , *FAMILIES , *RENAL tubular transport disorders , *MUSCLES - Abstract
• Two families with cylindrical spirals on muscle biopsy and suspected genetic cause. • Association of the EBF3 neurodevelopmental syndrome with cylindrical spirals. • Clinical investigation of patients with rare ultra-structural muscle features. Cylindrical spirals are a rare ultrastructural finding on muscle biopsy, with fewer than 20 reported cases since its first description in 1979. These structures are sometimes observed with tubular aggregates and are thought to comprise longitudinal sarcoplasmic reticulum. While mutations in genes encoding key components of Ca2+ handling (ORAI1 and STIM1) underlie tubular aggregate myopathy, no causative genes have been associated with cylindrical spirals. Here we describe two families with cylindrical spirals on muscle biopsy with a suspected genetic cause. In one family we identified a known truncating variant in EBF3 , previously associated with a neurodevelopmental disorder. The affected individuals in this family present with clinical features overlapping with those described for EBF3 disease. An isolated proband in the second family harbours bi-allelic truncating variants in TTN and her clinical course and other features on biopsy are highly concordant for titinopathy. From experimental studies, EBF3 is known to be involved in Ca2+ regulation in muscle, thus EBF3 dysregulation may represent a novel mechanism of impaired Ca2+ handling leading to cylindrical spirals. Additional cases of EBF3 disease or titinopathy with cylindrical spirals need to be identified to support the involvement of these genes in the pathogenesis of cylindrical spirals. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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34. A new mutation of the SCGA gene is the cause of a late onset mild phenotype limb girdle muscular dystrophy type 2D with axial involvement.
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Gonzalez-Quereda, Lidia, Gallardo, Eduard, Töpf, Ana, Alonso-Jimenez, Alicia, Straub, Volker, Rodriguez, Maria Jose, Lleixa, Cinta, Illa, Isabel, Gallano, Pia, and Diaz-Manera, Jordi
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- *
MUSCULAR dystrophy , *MUSCLE diseases , *SARCOGLYCANS , *BIOPSY , *NUCLEOTIDE sequencing - Abstract
Highlights • Our study expands the knowledge on clinical presentation of patients with mutations in the SGCA gene. • This report widens the diagnostic algorithm available for patients with primary axial myopathy. • Clinical data notably enriches the interpretation of exome analysis. • Partial expression of alpha-sarcoglycan could be enough to modify the phenotype. Abstract Mutations in the SGCA gene cause limb girdle muscular dystrophy type 2D (LGMD2D). We report a family with three affected siblings with a mild phenotype consisting of late onset glutei and axial muscle weakness produced by a new mutation in the SGCA gene leading to a partial expression of the alpha-sarcoglycan protein. The MRI showed muscle atrophy involving paraspinal, pelvic and thigh muscles and a dystrophic pattern was observed in the muscle biopsy. Exome sequencing revealed a homozygous intronic deletion of SGCA and mRNA analysis showed the presence of three different transcripts. The presence, though in a lower proportion, of wild type transcript leads to a milder presentation of the disease. Although clinical symptoms did not entirely correspond with a sarcoglycanopathy, a compatible muscle MRI drove us to look for changes in the sarcoglycan genes. These cases are an example of how clinical, radiological and pathological data enriches the interpretation of exome analysis. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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35. New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy patients
- Author
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Laura Costa-Comellas, Chiara Panicucci, Ana Camacho-Salas, Ulrike Schara, Claudio Semplicini, Isabel Illa, Arturo Fraga-Bau, Leroy ten Dam, Jan De Bleecker, Lea Leonardis, Jesper Helbo Storgaard, Juan Carlos de Leon-Hernández, Vittoria Zangaro, Giacomo P. Comi, Vincenzo Nigro, Adele D'Amico, Benedikt Schoser, Pia Gallano, Manuela Santos, Edoardo Malfatti, Cristina Domínguez-González, F. Munell, De Vos Elke, Alicia Alonso-Jimenez, Matteo Garibaldi, Bjarne Udd, Nicoline Løkken, A. J. van der Kooi, Giorgio Tasca, John Vissing, Jordi Díaz-Manera, Elena Pegoraro, Andrea Gangfuß, Jorge Alonso-Pérez, Claudia Weiss, Luisa Politano, Marie Rohlenová, Cristina Garrido, David Gómez-Andrés, Jana Haberlová, Roberto Fernández-Torrón, Gabriele Dekomien, Kristl G. Claeys, Marianne de Visser, Andrés Nascimento, Michela Guglieri, Carlos Ortez, Isabelle Richard, Lidia Gonzalez-Quereda, Béla Melegh, Claudio Bruno, Omar Abdel-Mannan, Anna Sarkozy, Adolfo López de Munain, Blaz Koritnik, Nicolas Deconinck, Kinga Hadzsiev, Luca Bello, Johanna Palmio, Volker Straub, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Neurology, ANS - Neuroinfection & -inflammation, Graduate School, Alonso-Pérez, Jorge, González-Quereda, Lidia, Bello, Luca, Guglieri, Michela, Straub, Volker, Gallano, Pia, Semplicini, Claudio, Pegoraro, Elena, Zangaro, Vittoria, Nascimento, André, Ortez, Carlo, Comi, Giacomo Pietro, ten Dam, Leroy, De Visser, Marianne, van der Kooi, A J, Garrido, Cristina, Santos, Manuela, Schara, Ulrike, Gangfuß, Andrea, Løkken, Nicoline, Storgaard, Jesper Helbo, Vissing, John, Schoser, Benedikt, Dekomien, Gabriele, Udd, Bjarne, Palmio, Johanna, D'Amico, Adele, Politano, Luisa, Nigro, Vincenzo, Bruno, Claudio, Panicucci, Chiara, Sarkozy, Anna, Abdel-Mannan, Omar, Alonso-Jimenez, Alicia, Claeys, Kristl G, Gomez-Andrés, David, Munell, Francina, Costa-Comellas, Laura, Haberlová, Jana, Rohlenová, Marie, Elke, De Vo, De Bleecker, Jan L, Dominguez-González, Cristina, Tasca, Giorgio, Weiss, Claudia, Deconinck, Nicola, Fernández-Torrón, Roberto, López de Munain, Adolfo, Camacho-Salas, Ana, Melegh, Béla, Hadzsiev, Kinga, Leonardis, Lea, Koritnik, Blaz, Garibaldi, Matteo, de Leon-Hernández, Juan Carlo, Malfatti, Edoardo, Fraga-Bau, Arturo, Richard, Isabelle, Illa, Isabel, and Díaz-Manera, Jordi
- Subjects
0301 basic medicine ,Registrie ,Male ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,Medizin ,Limb girdle muscular dystrophie ,Cohort Studies ,0302 clinical medicine ,Registries ,Child ,sarcoglycan ,ComputingMilieux_MISCELLANEOUS ,treatment ,Cohort ,cohort ,Middle Aged ,limb girdle muscular dystrophies ,3. Good health ,Europe ,Child, Preschool ,registries ,Female ,Cohort study ,Sarcoglycanopathies ,Adult ,medicine.medical_specialty ,Adolescent ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Humans ,Limb girdle muscular dystrophies ,Sarcoglycan ,Genetic Association Studies ,SGCA ,Aged ,Retrospective Studies ,business.industry ,Retrospective cohort study ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,Treatment ,030104 developmental biology ,Sarcoglycanopathy ,Muscular Dystrophies, Limb-Girdle ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Neurology (clinical) ,Human medicine ,Age of onset ,business ,030217 neurology & neurosurgery ,Limb-girdle muscular dystrophy - Abstract
Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3–6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.
- Published
- 2020
36. Dystrophinopathy Phenotypes and Modifying Factors in DMD Exon 45-55 Deletion.
- Author
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Poyatos-García J, Martí P, Liquori A, Muelas N, Pitarch I, Martinez-Dolz L, Rodríguez B, Gonzalez-Quereda L, Damiá M, Aller E, Selva-Gimenez M, Vilchez R, Diaz-Manera J, Alonso-Pérez J, Barcena JE, Jauregui A, Gámez J, Aladrén JA, Fernández A, Montolio M, Azorin I, Hervas D, Casasús A, Nieto M, Gallano P, Sevilla T, and Vilchez JJ
- Subjects
- Humans, Dystrophin genetics, Dystrophin metabolism, Cohort Studies, Cross-Sectional Studies, Exons genetics, Phenotype, Actinin genetics, RNA, Long Noncoding, Muscular Dystrophy, Duchenne metabolism
- Abstract
Objective: Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset., Methods: This cross-sectional, multicenter cohort study applied clinical and functional evaluation. Next generation sequencing was employed to identify intronic breakpoints and their impact on the Dp140 promotor, intronic long noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4, ACTN3) and concomitant mutations were also assessed. Haplotypes were built using DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via immunostaining, Western blotting, reverse transcription polymerase chain reaction (PCR), and droplet digital PCR in 9 muscle biopsies., Results: The series comprised 57 subjects (23 index) expressing Becker phenotype (28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive impairment occurred in 90% of children. Patients were classified according to 10 distinct index-case breakpoints; 4 of them were recurrent due to founder events. A specific breakpoint (D5) was associated with severity, but no significant effect was appreciated due to the changes in intronic sequences. All biopsies showed dystrophin expression of >67% and traces of alternative del45-57 transcript that were not deemed pathogenically relevant. Only the LTBP4 haplotype appeared associated the presence of cardiopathy among the explored extragenic factors., Interpretation: We confirmed that del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved. ANN NEUROL 2022;92:793-806., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
- Published
- 2022
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37. Systematic Collaborative Reanalysis of Genomic Data Improves Diagnostic Yield in Neurologic Rare Diseases.
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Bullich G, Matalonga L, Pujadas M, Papakonstantinou A, Piscia D, Tonda R, Artuch R, Gallano P, Garrabou G, González JR, Grinberg D, Guitart M, Laurie S, Lázaro C, Luengo C, Martí R, Milà M, Ovelleiro D, Parra G, Pujol A, Tizzano E, Macaya A, Palau F, Ribes A, Pérez-Jurado LA, and Beltran S
- Subjects
- Computational Biology, Exome, Humans, Exome Sequencing, Genomics, Rare Diseases diagnosis, Rare Diseases genetics
- Abstract
Many patients experiencing a rare disease remain undiagnosed even after genomic testing. Reanalysis of existing genomic data has shown to increase diagnostic yield, although there are few systematic and comprehensive reanalysis efforts that enable collaborative interpretation and future reinterpretation. The Undiagnosed Rare Disease Program of Catalonia project collated previously inconclusive good quality genomic data (panels, exomes, and genomes) and standardized phenotypic profiles from 323 families (543 individuals) with a neurologic rare disease. The data were reanalyzed systematically to identify relatedness, runs of homozygosity, consanguinity, single-nucleotide variants, insertions and deletions, and copy number variants. Data were shared and collaboratively interpreted within the consortium through a customized Genome-Phenome Analysis Platform, which also enables future data reinterpretation. Reanalysis of existing genomic data provided a diagnosis for 20.7% of the patients, including 1.8% diagnosed after the generation of additional genomic data to identify a second pathogenic heterozygous variant. Diagnostic rate was significantly higher for family-based exome/genome reanalysis compared with singleton panels. Most new diagnoses were attributable to recent gene-disease associations (50.8%), additional or improved bioinformatic analysis (19.7%), and standardized phenotyping data integrated within the Undiagnosed Rare Disease Program of Catalonia Genome-Phenome Analysis Platform functionalities (18%)., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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38. Clinical and genetic spectrum of a large cohort of patients with δ-sarcoglycan muscular dystrophy.
- Author
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Alonso-Pérez J, González-Quereda L, Bruno C, Panicucci C, Alavi A, Nafissi S, Nilipour Y, Zanoteli E, Isihi LMA, Melegh B, Hadzsiev K, Muelas N, Vílchez JJ, Dourado ME, Kadem N, Kutluk G, Umair M, Younus M, Pegorano E, Bello L, Crawford TO, Suárez-Calvet X, Töpf A, Guglieri M, Marini-Bettolo C, Gallano P, Straub V, and Díaz-Manera J
- Subjects
- Adult, Child, Humans, Muscle Weakness, Retrospective Studies, Sarcoglycans genetics, Sarcoglycans metabolism, Muscular Dystrophies genetics, Muscular Dystrophies, Limb-Girdle diagnosis, Muscular Dystrophies, Limb-Girdle genetics, Sarcoglycanopathies genetics
- Abstract
Sarcoglycanopathies include four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent and is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic spectrum of a large international cohort of LGMDR6 patients and to investigate whether or not genetic or protein expression data could predict a disease's severity. This is a retrospective study collecting demographic, genetic, clinical and histological data of patients with genetically confirmed LGMDR6 including protein expression data from muscle biopsies. We contacted 128 paediatric and adult neuromuscular units around the world that reviewed genetic data of patients with a clinical diagnosis of a neuromuscular disorder. We identified 30 patients with a confirmed diagnosis of LGMDR6 of which 23 patients were included in this study. Eighty-seven per cent of the patients had consanguineous parents. Ninety-one per cent of the patients were symptomatic at the time of the analysis. Proximal muscle weakness of the upper and lower limbs was the most common presenting symptom. Distal muscle weakness was observed early over the course of the disease in 56.5% of the patients. Cardiac involvement was reported in five patients (21.7%) and four patients (17.4%) required non-invasive ventilation. Sixty per cent of patients were wheelchair-bound since early teens (median age of 12.0 years). Patients with absent expression of the sarcoglycan complex on muscle biopsy had a significant earlier onset of symptoms and an earlier age of loss of ambulation compared to patients with residual protein expression. This study confirmed that delta-sarcoglycanopathy is an ultra-rare neuromuscular condition and described the clinical and molecular characteristics of the largest yet-reported collected cohort of patients. Our results showed that this is a very severe and quickly progressive disease characterized by generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs. Similar to other forms of sarcoglycanopathies, the severity and rate of progressive weakness correlates inversely with the abundance of protein on muscle biopsy., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2022
- Full Text
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39. New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.
- Author
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Alonso-Pérez J, González-Quereda L, Bello L, Guglieri M, Straub V, Gallano P, Semplicini C, Pegoraro E, Zangaro V, Nascimento A, Ortez C, Comi GP, Dam LT, De Visser M, van der Kooi AJ, Garrido C, Santos M, Schara U, Gangfuß A, Løkken N, Storgaard JH, Vissing J, Schoser B, Dekomien G, Udd B, Palmio J, D'Amico A, Politano L, Nigro V, Bruno C, Panicucci C, Sarkozy A, Abdel-Mannan O, Alonso-Jimenez A, Claeys KG, Gomez-Andrés D, Munell F, Costa-Comellas L, Haberlová J, Rohlenová M, Elke V, De Bleecker JL, Dominguez-González C, Tasca G, Weiss C, Deconinck N, Fernández-Torrón R, López de Munain A, Camacho-Salas A, Melegh B, Hadzsiev K, Leonardis L, Koritnik B, Garibaldi M, de Leon-Hernández JC, Malfatti E, Fraga-Bau A, Richard I, Illa I, and Díaz-Manera J
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Cohort Studies, Europe epidemiology, Female, Humans, Male, Middle Aged, Muscular Dystrophies, Limb-Girdle diagnosis, Muscular Dystrophies, Limb-Girdle epidemiology, Muscular Dystrophies, Limb-Girdle genetics, Retrospective Studies, Sarcoglycanopathies diagnosis, Young Adult, Genetic Association Studies methods, Sarcoglycanopathies epidemiology, Sarcoglycanopathies genetics
- Abstract
Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2020
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- View/download PDF
40. Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain.
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Gonzalez-Quereda L, Rodriguez MJ, Diaz-Manera J, Alonso-Perez J, Gallardo E, Nascimento A, Ortez C, Natera-de Benito D, Olive M, Gonzalez-Mera L, Munain AL, Zulaica M, Poza JJ, Jerico I, Torne L, Riera P, Milisenda J, Sanchez A, Garrabou G, Llano I, Madruga-Garrido M, and Gallano P
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Genetic Association Studies methods, Humans, Infant, Infant, Newborn, Male, Middle Aged, Mitochondrial Diseases diagnosis, Mitochondrial Diseases epidemiology, Mitochondrial Diseases genetics, Muscular Diseases diagnosis, Muscular Diseases epidemiology, Muscular Diseases genetics, Neuromuscular Diseases diagnosis, Neuromuscular Diseases epidemiology, Spain epidemiology, Young Adult, DNA Mutational Analysis methods, High-Throughput Nucleotide Sequencing methods, Mutation, Neuromuscular Diseases genetics
- Abstract
The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN , NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients' clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.
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- 2020
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41. Interplay between DMD point mutations and splicing signals in Dystrophinopathy phenotypes.
- Author
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Juan-Mateu J, González-Quereda L, Rodríguez MJ, Verdura E, Lázaro K, Jou C, Nascimento A, Jiménez-Mallebrera C, Colomer J, Monges S, Lubieniecki F, Foncuberta ME, Pascual-Pascual SI, Molano J, Baiget M, and Gallano P
- Subjects
- Dystrophin metabolism, Exons, Female, Frameshift Mutation, Genotype, Humans, Male, Muscular Dystrophy, Duchenne pathology, Mutation, Missense, RNA Splice Sites, Dystrophin genetics, Muscular Dystrophy, Duchenne genetics, Muscular Dystrophy, Duchenne metabolism, Phenotype, Point Mutation, RNA Splicing
- Abstract
DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements.
- Published
- 2013
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