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

J Allergy Clin Immunol. 2022 Jul;150(1):223-228. doi: 10.1016/j.jaci.2022.01.024. Epub 2022 Feb 12.


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.

Keywords: CDC42; Golgi apparatus; HLH; MAS; NOCARH syndrome; anakinra; autoinflammation; cytopenia; emapalumab; palmitoylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Hematopoiesis
  • Humans
  • Immune System Diseases*
  • Infant, Newborn
  • Lymphohistiocytosis, Hemophagocytic* / genetics
  • Mutation
  • cdc42 GTP-Binding Protein* / genetics


  • CDC42 protein, human
  • cdc42 GTP-Binding Protein