Characterization of novel pathogenic variants leading to caspase-8 cleavage-resistant RIPK1-induced autoinflammatory syndrome

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• dc.contributor.author Tapiz I Reula, Alfonso José
• dc.contributor.author Cochino, Alexis-Virgil
• dc.contributor.author Martins, Andreia L.
• dc.contributor.author Angosto-Bazarra, Diego
• dc.contributor.author Ortiz de Landazuri, Iñaki
• dc.contributor.author Mensa Vilaró, Anna
• dc.contributor.author Cabral, Marta
• dc.contributor.author Baroja-Mazo, Alberto
• dc.contributor.author Baños, María C.
• dc.contributor.author Lobato-Salinas, Zulema
• dc.contributor.author Fabregat, Virginia
• dc.contributor.author Plaza, Susana
• dc.contributor.author Yagüe, Jordi L.
• dc.contributor.author Casals López, Ferran
• dc.contributor.author Oliva Miguel, Baldomero
• dc.contributor.author Figueiredo, Antonio E.
• dc.contributor.author Pelegrín, Pablo
• dc.contributor.author Aróstegui Gorospe, Juan Ignacio
• dc.date.accessioned 2022-11-14T07:57:34Z
• dc.date.available 2022-11-14T07:57:34Z
• dc.date.issued 2022
• dc.description.abstract 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.
• dc.description.sponsorship Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work has been partially funded by the following: Grants from the Spanish Ministry of Science, Innovation and Universities and co-funded by the European Regional Development Fund / Agencia Estatal de Investigación: RTI2018-096824-B-C21 (JIA); RTI2018-096824-B-C22 (FC); SAF2017-88276-R (PP). Grant from the Spanish Ministry of Science and Innovation / Agencia Estatal de Investigación (10.13039/501100011033): PID2020-116709RB-I00 (PP). Grant from Instituto de Salud Carlos III and co-funded by the European Union: PI19/01567 (AM-V). Grants from Fundación Séneca: 20859/PI/18 (PP); 21081/PDC/19 (PP); 0003/COVI/20 (PP). Grants from European Research Council: ERC-2013-CoG 614578 (PP); ERC-2019-PoC 899636 (PP)
• dc.format.mimetype application/pdf
• dc.identifier.citation Tapiz I Reula AJ, Cochino AV, Martins AL, Angosto-Bazarra D, de Landazuri IO, et al. Characterization of novel pathogenic variants leading to caspase-8 cleavage-resistant RIPK1-induced autoinflammatory syndrome. J Clin Immunol. 2022 Oct;42(7):1421-32. DOI: 10.1007/s10875-022-01298-2
• dc.identifier.doi http://dx.doi.org/10.1007/s10875-022-01298-2
• dc.identifier.issn 0271-9142
• dc.identifier.uri http://hdl.handle.net/10230/54833
• dc.language.iso eng
• dc.publisher SpringerOpen
• dc.relation.ispartof J Clin Immunol. 2022 Oct;42(7):1421-32
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-096824-B-C21
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-096824-B-C22
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-88276-R
• dc.rights This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword RIPK1
• dc.subject.keyword Receptor-interacting kinases
• dc.subject.keyword Autoinflammatory diseases
• dc.subject.keyword Cleavage-resistant RIPK1-induced autoinflammatory syndrome
• dc.subject.keyword Necroptosis
• dc.title Characterization of novel pathogenic variants leading to caspase-8 cleavage-resistant RIPK1-induced autoinflammatory syndrome
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion