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

Pathogenic missense variants in cell division control protein 42 (CDC42) differentially affect protein function, causing distinct diseases variably affecting neurodevelopment, hematopoiesis, and immune response. We sought to classify clinically and functionally three pathogenic variants (p.R186C, p.C188Y, p.*192Cext*24) affecting the lipidation of the C-terminus of CDC42 to better delineate protein function and improve patient management. To this purpose, in vitro and in vivo studies and comparative analysis of the available clinical data and medical history of patients were performed. Unprenylated CDC42C188Y did not behave as a membrane-bound protein and was aberrantly accumulated to the nucleus, whereas the CDC42*192Cext*24 mutant replicated the CDC42R186C behaviour, being targeted to the Golgi apparatus in a palmitoylation dependent manner (Fig. 1) . p.C188Y and p.*192Cext*24 promoted accelerated protein degradation (Fig. 3A) . Assessment of in vitro polarized migration (Fig. 3B) and development in Caenorhabditis elegans (Fig. 4) documented a loss of-function behaviour of the p.C188Y and p.*192Cext*24 variants. Consistently with functional variability, the three pathogenic variants were associated with different clinical presentations, with dysmorphisms, severity, and age of onset of cytopenia and extent of autoinflammation representing major differences (Fig. 5) .