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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.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.issn 0271-9142
dc.identifier.uri http://hdl.handle.net/10230/54833
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.language.iso eng
dc.publisher SpringerOpen
dc.relation.ispartof J Clin Immunol. 2022 Oct;42(7):1421-32
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.uri http://creativecommons.org/licenses/by/4.0/
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.identifier.doi http://dx.doi.org/10.1007/s10875-022-01298-2
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.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.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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