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

Pathogenic RIPK1 variants have been described as the cause of two different inborn errors of immunity. Biallelic loss-of-function variants cause the recessively inherited RIPK1 deficiency, while monoallelic variants impairing the caspase-8-mediated RIPK1 cleavage provoke a novel autoinflammatory dis...

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Autores: Tapiz i Reula, Alfonso José, Virgil Cochino, Alexis, Martins, Andreia L., Angosto Bazarra, Diego, Ortiz de Landazuri, Iñaki, Mensa Vilaró, Anna, Cabral, Marta, Baroja Mazo, Alberto, Baños, María C., Lobato Salinas, Zulema, Fabregat, Virginia, Plaza, Susana, Yagüe, Jordi, Casals López, Ferran, Oliva, Baldomero, Figueiredo, Antonio E., Pelegrín, Pablo, Aróstegui Gorospe, Juan Ignacio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/213841
Acceso en línea:https://hdl.handle.net/2445/213841
Access Level:acceso abierto
Palabra clave:Inflamació
Apoptosi
Malalties hereditàries
Inflammation
Apoptosis
Genetic diseases
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spelling Characterization of Novel Pathogenic Variants Leading to Caspase-8 Cleavage-Resistant RIPK1-Induced Autoinflammatory SyndromeTapiz i Reula, Alfonso JoséVirgil Cochino, AlexisMartins, Andreia L.Angosto Bazarra, DiegoOrtiz de Landazuri, IñakiMensa Vilaró, AnnaCabral, MartaBaroja Mazo, AlbertoBaños, María C.Lobato Salinas, ZulemaFabregat, VirginiaPlaza, SusanaYagüe, JordiCasals López, FerranOliva, BaldomeroFigueiredo, Antonio E.Pelegrín, PabloAróstegui Gorospe, Juan IgnacioInflamacióApoptosiMalalties hereditàriesInflammationApoptosisGenetic diseasesPathogenic RIPK1 variants have been described as the cause of two different inborn errors of immunity. Biallelic loss-of-function variants cause the recessively inherited RIPK1 deficiency, while monoallelic variants impairing the caspase-8-mediated RIPK1 cleavage provoke a novel autoinflammatory disease (AID) called cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome. The aim of this study was to characterize the pathogenicity of two novel RIPK1 variants located at the cleavage site of caspase-8 detected in patients with dominantly-inherited, early-onset undefined AID. RIPK1 genotyping was performed by Sanger and next-generation sequencing. Clinical and analytical data were collected from medical charts, and in silico and in vitro assays were performed to evaluate the functional consequences. Genetic analyses identified two novel heterozygous RIPK1 variants at the caspase-8 cleavage site (p.Leu321Arg and p.Asp324Gly), which displayed a perfect intrafamilial phenotype-genotype segregation following a dominant inheritance pattern. Structural analyses suggested that these variants disrupt the normal RIPK1 structure, probably making it less accessible to and/or less cleavable by caspase-8. In vitro experiments confirmed that the p.Leu321Arg and p.Asp324Gly RIPK1 variants were resistant to caspase-8-mediated cleavage and induced a constitutive activation of necroptotic pathway in a similar manner that previously characterized RIPK1 variants causing CRIA syndrome. All these results strongly supported the pathogenicity of the two novel RIPK1 variants and the diagnosis of CRIA syndrome in all enrolled patients. Moreover, the evidences here collected expand the phenotypic and genetic diversity of this recently described AID, and provide interesting data about effectiveness of treatments that may benefit future patients.Springer Verlag2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/213841Articles publicats en revistes (Genètica, Microbiologia i Estadística)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a:Journal of Clinical Immunology, 2022, vol. 42, num.7, p. 1421-1432cc-by (c) Tapiz i Reula, Alfonso José et al., 2022https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2138412026-05-27T06:46:51Z
dc.title.none.fl_str_mv Characterization of Novel Pathogenic Variants Leading to Caspase-8 Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome
title Characterization of Novel Pathogenic Variants Leading to Caspase-8 Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome
spellingShingle Characterization of Novel Pathogenic Variants Leading to Caspase-8 Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome
Tapiz i Reula, Alfonso José
Inflamació
Apoptosi
Malalties hereditàries
Inflammation
Apoptosis
Genetic diseases
title_short Characterization of Novel Pathogenic Variants Leading to Caspase-8 Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome
title_full Characterization of Novel Pathogenic Variants Leading to Caspase-8 Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome
title_fullStr Characterization of Novel Pathogenic Variants Leading to Caspase-8 Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome
title_full_unstemmed Characterization of Novel Pathogenic Variants Leading to Caspase-8 Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome
title_sort Characterization of Novel Pathogenic Variants Leading to Caspase-8 Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome
dc.creator.none.fl_str_mv Tapiz i Reula, Alfonso José
Virgil Cochino, Alexis
Martins, Andreia L.
Angosto Bazarra, Diego
Ortiz de Landazuri, Iñaki
Mensa Vilaró, Anna
Cabral, Marta
Baroja Mazo, Alberto
Baños, María C.
Lobato Salinas, Zulema
Fabregat, Virginia
Plaza, Susana
Yagüe, Jordi
Casals López, Ferran
Oliva, Baldomero
Figueiredo, Antonio E.
Pelegrín, Pablo
Aróstegui Gorospe, Juan Ignacio
author Tapiz i Reula, Alfonso José
author_facet Tapiz i Reula, Alfonso José
Virgil Cochino, Alexis
Martins, Andreia L.
Angosto Bazarra, Diego
Ortiz de Landazuri, Iñaki
Mensa Vilaró, Anna
Cabral, Marta
Baroja Mazo, Alberto
Baños, María C.
Lobato Salinas, Zulema
Fabregat, Virginia
Plaza, Susana
Yagüe, Jordi
Casals López, Ferran
Oliva, Baldomero
Figueiredo, Antonio E.
Pelegrín, Pablo
Aróstegui Gorospe, Juan Ignacio
author_role author
author2 Virgil Cochino, Alexis
Martins, Andreia L.
Angosto Bazarra, Diego
Ortiz de Landazuri, Iñaki
Mensa Vilaró, Anna
Cabral, Marta
Baroja Mazo, Alberto
Baños, María C.
Lobato Salinas, Zulema
Fabregat, Virginia
Plaza, Susana
Yagüe, Jordi
Casals López, Ferran
Oliva, Baldomero
Figueiredo, Antonio E.
Pelegrín, Pablo
Aróstegui Gorospe, Juan Ignacio
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Inflamació
Apoptosi
Malalties hereditàries
Inflammation
Apoptosis
Genetic diseases
topic Inflamació
Apoptosi
Malalties hereditàries
Inflammation
Apoptosis
Genetic diseases
description Pathogenic RIPK1 variants have been described as the cause of two different inborn errors of immunity. Biallelic loss-of-function variants cause the recessively inherited RIPK1 deficiency, while monoallelic variants impairing the caspase-8-mediated RIPK1 cleavage provoke a novel autoinflammatory disease (AID) called cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome. The aim of this study was to characterize the pathogenicity of two novel RIPK1 variants located at the cleavage site of caspase-8 detected in patients with dominantly-inherited, early-onset undefined AID. RIPK1 genotyping was performed by Sanger and next-generation sequencing. Clinical and analytical data were collected from medical charts, and in silico and in vitro assays were performed to evaluate the functional consequences. Genetic analyses identified two novel heterozygous RIPK1 variants at the caspase-8 cleavage site (p.Leu321Arg and p.Asp324Gly), which displayed a perfect intrafamilial phenotype-genotype segregation following a dominant inheritance pattern. Structural analyses suggested that these variants disrupt the normal RIPK1 structure, probably making it less accessible to and/or less cleavable by caspase-8. In vitro experiments confirmed that the p.Leu321Arg and p.Asp324Gly RIPK1 variants were resistant to caspase-8-mediated cleavage and induced a constitutive activation of necroptotic pathway in a similar manner that previously characterized RIPK1 variants causing CRIA syndrome. All these results strongly supported the pathogenicity of the two novel RIPK1 variants and the diagnosis of CRIA syndrome in all enrolled patients. Moreover, the evidences here collected expand the phenotypic and genetic diversity of this recently described AID, and provide interesting data about effectiveness of treatments that may benefit future patients.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/213841
url https://hdl.handle.net/2445/213841
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a:
Journal of Clinical Immunology, 2022, vol. 42, num.7, p. 1421-1432
dc.rights.none.fl_str_mv cc-by (c) Tapiz i Reula, Alfonso José et al., 2022
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Tapiz i Reula, Alfonso José et al., 2022
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Verlag
publisher.none.fl_str_mv Springer Verlag
dc.source.none.fl_str_mv Articles publicats en revistes (Genètica, Microbiologia i Estadística)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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