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1. Disease phenotypes in adult patients with suspected undifferentiated autoinflammatory diseases and PFAPA syndrome: Clinical and therapeutic implications

Author

Gómez-Caverzaschi, Verónica, Yagüe, Jordi, Espinosa, Gerard, Mayordomo-Bofill, Isabet, Bedón-Galarza, Ricardo, Araújo, Olga, Pelegrín, Laura, Arbelo, Elena, Morales, Xavier, Balagué, Olga, Figueras-Nart, Ignasi, Mascaró, José M., Fuertes, Irene, Giavedoni, Priscila, Muxí, Africa, Alobid, Isam, Vilaseca, Isabel, Cervera, Ricard, Aróstegui, Juan I., Mensa-Vilaró, Anna, and Hernández-Rodríguez, José

Published
2024
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2. Characterization of Novel Pathogenic Variants Leading to Caspase-8 Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome

Author

Tapiz i Reula, Alfonso José, Cochino, Alexis-Virgil, Martins, Andreia L., Angosto-Bazarra, Diego, de Landazuri, Iñaki Ortiz, Mensa-Vilaró, Anna, Cabral, Marta, Baroja-Mazo, Alberto, Baños, María C., Lobato-Salinas, Zulema, Fabregat, Virginia, Plaza, Susana, Yagüe, Jordi, Casals, Ferran, Oliva, Baldomero, Figueiredo, Antonio E., Pelegrín, Pablo, and Aróstegui, Juan I.

Published
2022
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3. Characterizing Protracted Febrile Myalgia: Fasciitis and Vasculitis of the Fascia and Muscle as Novel Histopathological Features.

Author

Hernández-Rodríguez, José, Mestre-Trabal, Lola, Gómez-Caverzaschi, Verónica, Araújo, Olga, Terenas, Magda, Robaina, Ricardo, Bolaños, Julio, Prieto-González, Sergio, Antón, Jordi, Yagüe, Jordi, Tomás, Xavier, Aldecoa, Iban, and Grau, Josep M.

Subjects
ACUTE phase proteins, FAMILIAL Mediterranean fever, GENETIC disorders, CHILD patients, ACHILLES tendon
Abstract

Background: Protracted febrile myalgia (PFM) is a rare but severe form of myalgia mainly occurring in pediatric patients with familial Mediterranean fever (FMF). PFM imaging and histopathological data remain scarce. Objectives: A comprehensive clinical, imaging, and histopathological characterization of PFM was performed by retrospectively analyzing a reference center cohort of adult patients with FMF and myalgia, and by a PubMed search of well-described cases with PFM. Results: Among 56 adults with FMF from our center, 32 (57.1%) experienced myalgia, which was generalized in 21 (37.5%) and affected lower limbs in 11 (19.6%) subjects. One (1.8%) patient suffered PFM, mainly affecting calves and Achilles tendons. From our patient's detailed information and the data from 123 PFM cases reported in the literature, PFM was characterized as usually presenting with fever and severe generalized myalgia, with occasional involvement of lower legs and calves. It is mainly associated (in >90% of cases) with the pathogenic mutation M694V in the MEFV gene. Raised acute phase reactants and normal creatine kinase levels are constant. High glucocorticoid doses are useful in most patients, and sustained colchicine treatment protects from PFM recurrences. MRI may identify a variable degree of muscle inflammatory changes, especially subfascial and myofascial lesions with extension to tendinous structures. PFM histopathology is characterized by T-cell rich inflammatory infiltrates and vasculitis mainly involving the fasciae and myofascial areas, with a lower muscle extent. Conclusions: PFM can occur in children and adults and appears to be clinically manifested as fasciitis/tendinitis caused by a vasculitis of the fasciae rather than a major muscle vasculitis. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Immunoparesis defined by heavy/light chain pair suppression in smoldering multiple myeloma shows initial isotype specificity and involves other isotypes in advanced disease

Author

Isola, Ignacio, Moreno, David F., Moga, Esther, Mena, Mari-Pau, Tovar, Natalia, Rodríguez-Lobato, Luis Gerardo, Oliver-Caldés, Aina, Salgado, M. Carmen, Brasó-Maristany, Fara, Yagüe, Jordi, Cibeira, M. Teresa, Prat, Aleix, Rosiñol, Laura, Bladé, Joan, and Fernández de Larrea, Carlos

Published
2021
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5. Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome.

Author

Cardona, Daniela Ospina, Rodriguez-Pinto, Ignasi, Iosim, Sonia, Bonet, Nuria, Mensa-Vilaro, Anna, Wong, Mei-Kay, Ho, Gary, Tormo, Marc, Yagüe, Jordi, Shon, Wonwoo, Wallace, Daniel J, Casals, Ferran, Beck, David B, Abuav, Rachel, and Arostegui, Juan I

Subjects
SWEET'S syndrome, GENOMICS, RESEARCH funding, AUTOINFLAMMATORY diseases, ENZYMES, FEVER, GENETIC variation, RNA, MESSENGER RNA, NUCLEOTIDES, AGE factors in disease, X-linked genetic disorders, GENETIC mutation, DISEASE relapse, INFLAMMATION, GENETIC testing, MOSAICISM, SYMPTOMS
Abstract

Objective Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a complex immune disorder consequence of somatic UBA1 variants. Most reported pathogenic UBA1 variants are missense or splice site mutations directly impairing the translational start site at p.Met41, with recent studies showing that these variants are frequent causes of recurrent inflammation in older individuals. Here we aimed to characterize a novel UBA1 variant found in two patients clinically presenting with VEXAS syndrome. Methods Patients' data were collected from direct assessments and from their medical charts. Genomics analyses were undertaken by both Sanger and amplicon-based deep sequencing, and mRNA studies were undertaken by both cDNA subcloning and mRNA sequencing. Results We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung inflammation responsive only to glucocorticoids. RNA analysis of the patients' samples indicated aberrant mRNA splicing leading to multiple in-frame transcripts, including a transcript retaining the full sequence of intron 4 and a different transcript with the deletion of the first 15 nucleotides of exon 5. Conclusion Here we describe abnormal UBA1 transcription as a consequence of the novel c.346-2A>G variant, identified in two patients with clinical features compatible with VEXAS syndrome. Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and provide support for a complete gene evaluation in those patients considered candidates for VEXAS syndrome. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations

Author

Martín-Nalda, Andrea, Fortuny, Claudia, Rey, Lourdes, Bunney, Tom D., Alsina, Laia, Esteve-Solé, Ana, Bull, Daniel, Anton, Maria Carmen, Basagaña, María, Casals, Ferran, Deyá, Angela, García-Prat, Marina, Gimeno, Ramon, Juan, Manel, Martinez-Banaclocha, Helios, Martinez-Garcia, Juan J, Mensa-Vilaró, Anna, Rabionet, Raquel, Martin-Begue, Nieves, Rudilla, Francesc, Yagüe, Jordi, Estivill, Xavier, García-Patos, Vicente, Pujol, Ramon M., Soler-Palacín, Pere, Katan, Matilda, Pelegrín, Pablo, Colobran, Roger, Vicente, Asun, and Arostegui, Juan I.

Published
2020
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7. Development of a Novel Anti-CD19 Chimeric Antigen Receptor: A Paradigm for an Affordable CAR T Cell Production at Academic Institutions

Author

Castella, Maria, Boronat, Anna, Martín-Ibáñez, Raquel, Rodríguez, Vanina, Suñé, Guillermo, Caballero, Miguel, Marzal, Berta, Pérez-Amill, Lorena, Martín-Antonio, Beatriz, Castaño, Julio, Bueno, Clara, Balagué, Olga, González-Navarro, Europa Azucena, Serra-Pages, Carles, Engel, Pablo, Vilella, Ramon, Benitez-Ribas, Daniel, Ortiz-Maldonado, Valentín, Cid, Joan, Tabera, Jaime, Canals, Josep M., Lozano, Miquel, Baumann, Tycho, Vilarrodona, Anna, Trias, Esteve, Campo, Elías, Menendez, Pablo, Urbano-Ispizua, Álvaro, Yagüe, Jordi, Pérez-Galán, Patricia, Rives, Susana, Delgado, Julio, and Juan, Manel

Published
2019
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8. Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases

Author

Mensa-Vilaró, Anna, Bravo García-Morato, María, de la Calle-Martin, Oscar, Franco-Jarava, Clara, Martínez-Saavedra, María Teresa, González-Granado, Luis I., González-Roca, Eva, Fuster, Jose Luis, Alsina, Laia, Mutchinick, Osvaldo M., Balderrama-Rodríguez, Angélica, Ramos, Eduardo, Modesto, Consuelo, Mesa-del-Castillo, Pablo, Ortego-Centeno, Norberto, Clemente, Daniel, Souto, Alejandro, Palmou, Natalia, Remesal, Agustín, Leslie, Kieron S., Gómez de la Fuente, Enrique, Yadira Bravo Gallego, Luz, Campistol, Josep María, Dhouib, Naouel Guirat, Bejaoui, Mohamed, Dutra, Lívia Almeida, Terreri, Maria Teresa, Mosquera, Catalina, González, Tatiana, Cañellas, Jerónima, García-Ruiz de Morales, José María, Wouters, Carine H., Bosque, María Teresa, Cham, Weng Tarng, Jiménez-Treviño, Santiago, de Inocencio, Jaime, Bloomfield, Markéta, Pérez de Diego, Rebeca, Martínez-Pomar, Natalia, Rodríguez-Pena, Rebeca, González-Santesteban, Cecilia, Soler-Palacín, Pere, Casals, Ferran, Yagüe, Jordi, Allende, Luis M., Rodríguez-Gallego, José Carlos, Colobran, Roger, Martínez-Martínez, Laura, López-Granados, Eduardo, and Aróstegui, Juan I.

Published
2019
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13. Case report: Novel compound heterozygous IL1RN mutations as the likely cause of a lethal form of deficiency of interleukin-1 receptor antagonist.

Author

Urbaneja, Elena, Bonet, Nuria, Solis-Moruno, Manuel, Mensa-Vilaro, Anna, Ortiz de Landazuri, Iñaki, Tormo, Marc, Lara, Rocio, Plaza, Susana, Fabregat, Virginia, Yagüe, Jordi, Casals, Ferran, and Arostegui, Juan I.

Subjects
INTERLEUKIN-1 receptors, DNA analysis, GENETIC variation, AUTOINFLAMMATORY diseases, NUCLEOTIDE sequencing, TEETH injuries
Abstract

Undiagnosed monogenic diseases represent a challenging group of human conditions highly suspicious to have a genetic origin, but without conclusive evidences about it. We identified two brothers born prematurely from a nonconsanguineous healthy couple, with a neonatal-onset, chronic disease characterized by severe skin and bone inflammatory manifestations and a fatal outcome in infancy. We conducted DNA and mRNA analyses in the patients' healthy relatives to identify the genetic cause of the patients' disease. DNA analyses were performed by both Sanger and next-generation sequencing, which identified two novel heterozygous IL1RN variants: the intronic c.318 + 2T>G variant in the father and a -2,600-bp intragenic deletion in the mother. IL1RN mRNA production was markedly decreased in both progenitors when compared with healthy subjects. The mRNA sequencing performed in each parent identified two novel, truncated IL1RN transcripts. Additional experiments revealed a perfect intrafamilial phenotype-genotype segregation following an autosomal recessive inheritance pattern. The evidences shown here supported for the presence of two novel loss-of-function (LoF) IL1RN pathogenic variants in the analyzed family. Biallelic LoF variants at the IL1RN gene cause the deficiency of interleukin-1 receptor antagonist (DIRA), a monogenic autoinflammatory disease with marked similarities with the patients described here. Despite the non-availability of the patients' samples representing the main limitation of this study, the collected evidences strongly suggest that the patients described here suffered from a lethal form of DIRA likely due to a compound heterozygous genotype at IL1RN, thus providing a reliable genetic diagnosis based on the integration of old medical information with currently obtained genetic data. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis

Author

Rabionet, Raquel, Remesal, Agustín, Mensa-Vilaró, Anna, Murías, Sara, Alcobendas, Rosa, González-Roca, Eva, Ruiz-Ortiz, Estibaliz, Antón, Jordi, Iglesias, Estibaliz, Modesto, Consuelo, Comas, David, Puig, Anna, Drechsel, Oliver, Ossowski, Stephan, Yagüe, Jordi, Merino, Rosa, Estivill, Xavier, and Arostegui, Juan I.

Published
2019
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19. Inherited biallelic CSF3Rmutations in severe congenital neutropenia

Author

Triot, Alexa, Järvinen, Päivi M., Arostegui, Juan I., Murugan, Dhaarini, Kohistani, Naschla, Dapena Díaz, José Luis, Racek, Tomas, Puchałka, Jacek, Gertz, E. Michael, Schäffer, Alejandro A., Kotlarz, Daniel, Pfeifer, Dietmar, Díaz de Heredia Rubio, Cristina, Ozdemir, Mehmet Akif, Patiroglu, Turkan, Karakukcu, Musa, Sánchez de Toledo Codina, José, Yagüe, Jordi, Touw, Ivo P., Unal, Ekrem, and Klein, Christoph

Published
2014
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22. Pyogenic Bacterial Infections in Humans with MyD88 Deficiency

Author

von Bernuth, Horst, Picard, Capucine, Jin, Zhongbo, Pankla, Rungnapa, Xiao, Hui, Ku, Cheng-Lung, Chrabieh, Maya, Mustapha, Imen Ben, Ghandil, Pegah, Camcioglu, Yildiz, Vasconcelos, Júlia, Sirvent, Nicolas, Guedes, Margarida, Vitor, Artur Bonito, Herrero-Mata, María José, Aróstegui, Juan Ignacio, Rodrigo, Carlos, Alsina, Laia, Ruiz-Ortiz, Estibaliz, Juan, Manel, Fortuny, Claudia, Yagüe, Jordi, Antón, Jordi, Pascal, Mariona, Chang, Huey-Hsuan, Janniere, Lucile, Rose, Yoann, Garty, Ben-Zion, Chapel, Helen, Issekutz, Andrew, Maródi, László, Rodriguez-Gallego, Carlos, Banchereau, Jacques, Abel, Laurent, Li, Xiaoxia, Chaussabel, Damien, Puel, Anne, and Casanova, Jean-Laurent

Published
2008
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27. Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes

Author

Nakagawa, Kenji, Gonzalez-Roca, Eva, Souto, Alejandro, Kawai, Toshinao, Umebayashi, Hiroaki, Campistol, Josep María, Cañellas, Jeronima, Takei, Syuji, Kobayashi, Norimoto, Callejas-Rubio, Jose Luis, Ortego-Centeno, Norberto, Ruiz-Ortiz, Estíbaliz, Rius, Fina, Anton, Jordi, Iglesias, Estibaliz, Jimenez-Treviño, Santiago, Vargas, Carmen, Fernandez-Martin, Julian, Calvo, Inmaculada, Hernández-Rodríguez, José, Mendez, María, Dordal, María Teresa, Basagaña, Maria, Bujan, Segundo, Yashiro, Masato, Kubota, Tetsuo, Koike, Ryuji, Akuta, Naoko, Shimoyama, Kumiko, Iwata, Naomi, Saito, Megumu K, Ohara, Osamu, Kambe, Naotomo, Yasumi, Takahiro, Izawa, Kazushi, Kawai, Tomoki, Heike, Toshio, Yagüe, Jordi, Nishikomori, Ryuta, and Aróstegui, Juan I

Published
2015
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30. Common variants in NLRP2 and NLRP3 genes are strong prognostic factors for the outcome of HLA-identical sibling allogeneic stem cell transplantation

Author

Granell, Miquel, Urbano-Ispizua, Álvaro, Pons, Aina, Aróstegui, Juan Ignacio, Gel, Bernat, Navarro, Alfons, Jansa, Sonia, Artells, Rosa, Gaya, Anna, Talarn, Carme, Fernández-Avilés, Francesc, Martínez, Carmen, Rovira, Montserrat, Carreras, Enric, Rozman, Ciril, Juan, Manel, Yagüe, Jordi, Montserrat, Emili, and Monzó, Mariano

Published
2008
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32. Chilblains outbreak during COVID‐19 pandemic: A Type‐I interferonopathy?

Author

Mensa‐Vilaró, Anna, Vicente, Asunción, Español‐Rego, Marta, Antón, Jordi, Fabregat, Virginia, Fortuny, Claudia, González, Europa Azucena, Fumadó, Victoria, González‐Roca, Eva, Jou, Cristina, Plaza, Susana, Mosquera, Juan Manuel, Yagüe, Jordi, Prat, Carolina, Pascal, Mariona, Juan, Manel, Arostegui, Juan I., Baselga, Eulalia, and Alsina, Laia

Subjects
COVID-19 pandemic, FOOT pain, MULTISYSTEM inflammatory syndrome in children, COVID-19
Abstract

They showed type-I IFN polarization in COVID-toes patients compared with HC.13 We assessed whole blood type-I IFN signature based on the expression of 28 ISG (Table S7) in 24 patients, and we observed that 29.2% (7/24) of enrolled patients displayed increased ISG scores (Table S4 and Figure S1). Patients with COVID-toes evaluated before 7 days of onset of the skin lesions show statistical increase in 28-IRG score compared with patients who started later than 7 days. On the other hand, the strengths of our study are that we describe a relatively big and homogeneous cohort of young patients with COVID-toes, and to our knowledge, this is the first report that examines IFN signature in pediatric patients with COVID-toes. [Extracted from the article]

Published
2022
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37. Somatic NOD2 mosaicism in Blau syndrome

Author

de Inocencio, Jaime, Mensa-Vilaro, Anna, Tejada-Palacios, Pilar, Enriquez-Merayo, Eugenia, González-Roca, Eva, Magri, Giuliana, Ruiz-Ortiz, Estibaliz, Cerutti, Andrea, Yagüe, Jordi, and Aróstegui, Juan I.

Published
2015
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40. Long-Term Responders After Autologous Stem Cell Transplantation in Multiple Myeloma.

Author

Oliver-Caldes, Aina, Soler-Perromat, Juan Carlos, Lozano, Ester, Moreno, David, Bataller, Alex, Mozas, Pablo, Garrote, Marta, Setoain, Xavier, Aróstegui, Juan Ignacio, Yagüe, Jordi, Tovar, Natalia, Jiménez, Raquel, Gerardo Rodríguez-Lobato, Luis, Cibeira, M. Teresa, Rosiñol, Laura, Bladé, Joan, Juan, Manel, and Fernández de Larrea, Carlos

Subjects
STEM cell transplantation, MULTIPLE myeloma, BONE marrow cells, LACTATE dehydrogenase, C-reactive protein, TIBIAL plateau fractures, PLASMACYTOMA
Abstract

Introduction: Multiple myeloma (MM) is considered an incurable hematological neoplasm. For transplant-eligible patients, initial treatment includes an induction phase followed by an autologous stem cell transplantation (ASCT). Despite the introduction of several drugs in the past years, relapses still occur. Nevertheless, some patients achieve sustained responses after successful induction treatment and ASCT. Methods: We retrospectively evaluated all patients diagnosed with MM in our institution who underwent induction treatment and ASCT between 1990 and 2015. The subset of patients who achieved a sustained response (any degree) for 5 or more years after ASCT without further treatment or signs of progression were distinguished as "long-term responders" (LTRs). In the non-LTR group, a cohort referred to as "prolonged responders" (PLRs) showed sustained response of at least 5 years after ASCT but eventually relapsed. We collected and analyzed clinical and laboratory data. Results: Two hundred and fifty patients were diagnosed with MM and received induction treatment and ASCT at our institution in the study period. Among them, 54 (21.6%) patients met the criteria for LTR. Some diagnostic features such as a younger age, female gender, ECOG performance status of 0, lower International Staging System (ISS) stage, lower bone marrow plasma cell infiltration, and lower serum levels of calcium, C-reactive protein, and lactate dehydrogenase (LDH) were found to be more prevalent in LTR. Female gender, an ECOG performance status of 0, a localized Durie-Salmon stage, an ISS of I-II, the absence of bone disease, and an LDH within normal range were also predictive of longer progression-free survival (PFS) and overall survival (OS) in the whole cohort. The depth of the response achieved after induction and ASCT as well as the administration of an IMID-based maintenance regimen may play a role in the differences observed on PFS between cohorts. A detectable M-protein with a monoclonal gammopathy of undetermined significance (MGUS)-like behavior was detected in one-third of LTR after ASCT. Although relapses continue to occur in patients who achieve a 5-year treatmentfree period after ASCT, a plateau is observed in the survival curves at approximately 21 years of follow-up. [ABSTRACT FROM AUTHOR]

Published
2022
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44. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

Author

Puente, Xose S., Pinyol, Magda, Quesada, Víctor, Conde, Laura, Ordóñez, Gonzalo R., Villamor, Neus, Escaramis, Georgia, Jares, Pedro, Beà, Sílvia, González-Díaz, Marcos, Bassaganyas, Laia, Baumann, Tycho, Juan, Manel, López-Guerra, Mónica, Colomer, Dolors, Tubío, José M. C., López, Cristina, Navarro, Alba, Tornador, Cristian, Aymerich, Marta, Rozman, María, Hernández, Jesús M., Puente, Diana A., Freije, José M. P., Velasco, Gloria, Gutiérrez-Fernández, Ana, Costa, Dolors, Carrió, Anna, Guijarro, Sara, Enjuanes, Anna, Hernández, Lluís, Yagüe, Jordi, Nicolás, Pilar, Romeo-Casabona, Carlos M., Himmelbauer, Heinz, Castillo, Ester, Dohm, Juliane C., de Sanjosé, Silvia, Piris, Miguel A., de Alava, Enrique, Miguel, Jesús San, Royo, Romina, Gelpí, Josep L., Torrents, David, Orozco, Modesto, Pisano, David G., Valencia, Alfonso, Guigó, Roderic, Bayés, Mónica, Heath, Simon, Gut, Marta, Klatt, Peter, Marshall, John, Raine, Keiran, Stebbings, Lucy A., Futreal, Andrew P., Stratton, Michael R., Campbell, Peter J., Gut, Ivo, López-Guillermo, Armando, Estivill, Xavier, Montserrat, Emili, López-Otín, Carlos, and Campo, Elías

Published
2011
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45. A somatic NLRP3 mutation as a cause of a sporadic case of chronic infantile neurologic, cutaneous, articular syndrome/neonatal-onset multisystem inflammatory disease: Novel evidence of the role of low-level mosaicism as the pathophysiologic mechanism underlying mendelian inherited diseases

Author

Aróstegui, Juan I., Lopez Saldaña, Ma Dolores, Pascal, Mariona, Clemente, Daniel, Aymerich, Marta, Balaguer, Francesc, Goel, Ajay, Fournier del Castillo, Concepción, Rius, Josefa, Plaza, Susana, López Robledillo, Juan Carlos, Juan, Manel, Ibañez, Mercedes, and Yagüe, Jordi

Published
2010
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46. First Description of Late‐Onset Autoinflammatory Disease Due to Somatic NLRC4 Mosaicism.

Author

Ionescu, Daniela, Peñín‐Franch, Alejandro, Mensa‐Vilaró, Anna, Castillo, Paola, Hurtado‐Navarro, Laura, Molina‐López, Cristina, Romero‐Chala, Silvia, Plaza, Susana, Fabregat, Virginia, Buján, Segundo, Marques, Joana, Casals, Ferran, Yagüe, Jordi, Oliva, Baldomero, Fernández‐Pereira, Luis Miguel, Pelegrín, Pablo, and Aróstegui, Juan I.

Subjects
MOSAICISM, GENETICS, SEQUENCE analysis, IN vivo studies, FEVER, DIARRHEA, DELAYED onset of disease, SIGNAL peptides, JOINT pain, ALLELES, IMMUNITY, ABDOMINAL pain, AUTOINFLAMMATORY diseases
Abstract

Objective: Autoinflammatory diseases are inherited disorders of innate immunity that usually start during childhood. However, several recent reports have described an increasing number of patients with autoinflammatory disease starting in adulthood. This study was undertaken to investigate the underlying cause of a case of late‐onset uncharacterized autoinflammatory disease. Methods: Genetics studies were performed using Sanger sequencing and next‐generation sequencing (NGS) methods. In silico, in vitro, and ex vivo analyses were performed to determine the functional consequences of the detected variant. Results: We studied a 57‐year‐old woman who at the age of 47 years began to have recurrent episodes of fever, myalgias, arthralgias, diffuse abdominal pain, diarrhea, adenopathies, and systemic inflammation, which were relatively well controlled with anti–interleukin‐1 (anti‐IL‐1) drugs. NGS analyses did not detect germline variants in any of the known autoinflammatory disease–associated genes, but they identified the p.Ser171Phe NLRC4 variant in unfractionated blood, with an allele fraction (2–4%) compatible with gene mosaicism. Structural modeling analyses suggested that this missense variant might favor the open, active conformation of the NLRC4 protein, and in vitro and ex vivo analyses confirmed its propensity to oligomerize and activate the NLRC4 inflammasome, with subsequent overproduction of IL‐18. Conclusion: Our findings indicate that the postzygotic p.Ser171Phe NLRC4 variant is a plausible cause of the disease in the enrolled patient. Functional and structural studies clearly support, for the first time, its gain‐of‐function behavior, consistent with previously reported NLRC4 pathogenic variants. These novel findings should be considered in the diagnostic evaluation of patients with adult‐onset uncharacterized autoinflammatory disease. [ABSTRACT FROM AUTHOR]

Published
2022
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47. Pyogenic Bacterial Infections in Humans with MyD88 Deficiency

Author

Bernuth, Horst von, Picard, Capucine, Jin, Zhongbo, Pankla, Rungnapa, Xiao, Hui, Ku, Cheng-Lung, Chrabieh, Maya, Mustapha, Imen Ben, Ghandil, Pegah, Camcioglu, Yildiz, Vasconcelos, Júlia, Sirvent, Nicolas, Guedes, Margarida, Vitor, Artur Bonito, Herrero-Mata, María José, Aróstegui, Juan Ignacio, Rodrigo, Carlos, Alsina, Laia, Ruiz-Ortiz, Estibaliz, Juan, Manel, Fortuny, Claudia, Yagüe, Jordi, Antón, Jordi, Pascal, Mariona, Chang, Huey-Hsuan, Janniere, Lucile, Rose, Yoann, Garty, Ben-Zion, Chapel, Helen, Issekutz, Andrew, Maródi, László, Rodriguez-Gallego, Carlos, Banchereau, Jacques, Abel, Laurent, Li, Xiaoxia, Chaussabel, Damien, Puel, Anne, and Casanova, Jean-Laurent

Published
2008
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