Background: Pathogenic missense variants in cell division control protein 42 (CDC42) differentially affect protein function, causing a clinically wide phenotypic spectrum variably affecting neurodevelopment, hematopoiesis, and immune response. More recently, 3 variants at the C-terminus of CDC42 were proposed to similarly impact protein function and cause a novel autoinflammatory disorder. Objectives: We sought to clinically and functionally classify these variants to improve patient management. Methods: Comparative analysis of the available clinical data and medical history of patients was performed. In vitro and in vivo studies were carried out to functionally characterize individual variants. Results: Differently from what had previously been observed for the p.R186C change causing neonatal-onset cytopenia, autoinflammation, and recurrent hemophagocytic lymphohistiocytosis, p.C188Y and p.∗192Cext∗24 promoted accelerated protein degradation. Unprenylated CDC42C188Y did not behave as a membrane-bound protein, whereas the residual CDC42∗192Cext∗24 mutant replicated the CDC42R186C behavior, being targeted to the Golgi apparatus in a palmitoylation-dependent manner. Assessment of in vitro polarized migration and development in Caenorhabditis elegans documented a loss-of-function behavior of the p.C188Y and p.∗192Cext∗24 variants. Consistently, the 3 pathogenic variants were associated with different clinical presentations, with dysmorphisms, severity, and age of onset of cytopenia and extent of autoinflammation representing major differences. Conclusions: Pathogenic variants at the CDC42 C-terminus differently impact protein stability, localization, and function, and cause different diseases, with p.R186C specifically associated with neonatal-onset pancytopenia and severe autoinflammation/hemophagocytic lymphohistiocytosis requiring emapalumab and bone marrow transplantation, and p.C188Y and p.∗192Cext∗24 causing anakinra-sensitive autoinflammation.

Mutations at the C-terminus of CDC42 cause distinct hematopoietic and autoinflammatory disorders / Coppola, S.; Insalaco, A.; Zara, E.; Di Rocco, M.; Marafon, D. P.; Spadaro, F.; Pannone, L.; Farina, L.; Pasquini, L.; Martinelli, S.; De Benedetti, F.; Tartaglia, M.. - In: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. - ISSN 0091-6749. - (2022). [10.1016/j.jaci.2022.01.024]

Mutations at the C-terminus of CDC42 cause distinct hematopoietic and autoinflammatory disorders

Zara E.;Di Rocco M.;Pannone L.;Farina L.;
2022

Abstract

Background: Pathogenic missense variants in cell division control protein 42 (CDC42) differentially affect protein function, causing a clinically wide phenotypic spectrum variably affecting neurodevelopment, hematopoiesis, and immune response. More recently, 3 variants at the C-terminus of CDC42 were proposed to similarly impact protein function and cause a novel autoinflammatory disorder. Objectives: We sought to clinically and functionally classify these variants to improve patient management. Methods: Comparative analysis of the available clinical data and medical history of patients was performed. In vitro and in vivo studies were carried out to functionally characterize individual variants. Results: Differently from what had previously been observed for the p.R186C change causing neonatal-onset cytopenia, autoinflammation, and recurrent hemophagocytic lymphohistiocytosis, p.C188Y and p.∗192Cext∗24 promoted accelerated protein degradation. Unprenylated CDC42C188Y did not behave as a membrane-bound protein, whereas the residual CDC42∗192Cext∗24 mutant replicated the CDC42R186C behavior, being targeted to the Golgi apparatus in a palmitoylation-dependent manner. Assessment of in vitro polarized migration and development in Caenorhabditis elegans documented a loss-of-function behavior of the p.C188Y and p.∗192Cext∗24 variants. Consistently, the 3 pathogenic variants were associated with different clinical presentations, with dysmorphisms, severity, and age of onset of cytopenia and extent of autoinflammation representing major differences. Conclusions: Pathogenic variants at the CDC42 C-terminus differently impact protein stability, localization, and function, and cause different diseases, with p.R186C specifically associated with neonatal-onset pancytopenia and severe autoinflammation/hemophagocytic lymphohistiocytosis requiring emapalumab and bone marrow transplantation, and p.C188Y and p.∗192Cext∗24 causing anakinra-sensitive autoinflammation.
2022
anakinra; autoinflammation; CDC42; cytopenia; emapalumab; Golgi apparatus; HLH; MAS; NOCARH syndrome; palmitoylation
01 Pubblicazione su rivista::01a Articolo in rivista
Mutations at the C-terminus of CDC42 cause distinct hematopoietic and autoinflammatory disorders / Coppola, S.; Insalaco, A.; Zara, E.; Di Rocco, M.; Marafon, D. P.; Spadaro, F.; Pannone, L.; Farina, L.; Pasquini, L.; Martinelli, S.; De Benedetti, F.; Tartaglia, M.. - In: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. - ISSN 0091-6749. - (2022). [10.1016/j.jaci.2022.01.024]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1617200
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