Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 150, Issue 1, Pages 223-228Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2022.01.024
Keywords
CDC42; NOCARH syndrome; autoinflammation; HLH; MAS; cytopenia; anakinra; emapalumab; palmitoylation; Golgi apparatus
Categories
Funding
- Italian Ministry of Health [5x1000]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG 21614]
- Italian Ministry of Research [FOE 2019]
- Fondazione Bambino Gesu
- Istituto Superiore di Sanita
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This study clinically and functionally classified three pathogenic variants of CDC42 at the C-terminus and found that they differently impact protein stability, localization, and function, causing various clinical diseases.
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 CDC42(C188Y) did not behave as a membrane-bound protein, whereas the residual CDC42(*192Cext*24) mutant replicated the CDC42(R186C) behavior, being targeted to the Golgi apparatus in a palmitoylationdependent manner. Assessment of in vitro polarized migration and development in Caenorhabditis elegans documented a lossof-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.
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