Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes

Abstract

Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.

A Novel CDC42 Mutation in an 11-Year Old Child Manifesting as Syndromic Immunodeficiency, Autoinflammation, Hemophagocytic Lymphohistiocytosis, and Malignancy: A Case Report

“…Further evidence supporting the notion that the CDC42 gene mutation causes a syndromic form of thrombocytopenia has also been provided by Takenouchi et al (4) and Motokawa et al (5) in their reports of the next two patients, sharing the same p.Tyr64Cys variant (6) and overlapping phenotypes including facial dysmorphism, psychomotor developmental delay, lymphedema of the lower extremities, camptodactyly, sensorineural hearing loss, and immunodeficiency. Further evidence for the intricate genotype-phenotype relationship and the heterogeneity of the clinical features correlating with mutations affecting the CDC42 gene was provided by Martinelli et al (7). The authors reported 15 patients, divided in three groups according to different disease-causing CDC42 mutations, namely, group I-p.Tyr64Cys, p.Arg66Gly, p.Arg68Gln, group II-p.Cys81Phe, p.Ser83Pro, p.Ala159Val, and group III-p.Ile21Thr, p.Tyr23Cys, pGlu171Lys.…”

“…The signaling and the regulatory function of CDC42 are based on its tightly regulated cycle of activation with GTP binding and an inactive state with GTP hydrolysis, and intricate interactions with multiple proteins that impact on cell functions during its active state (2). It has been shown that CDC42 plays a number of physiologically pivotal, tissuespecific roles in the cardiovascular, genitourinary, respiratory, nervous, and immune systems, and its dysfunction is implicated as a background for syndromic immunodeficiency and immune dysregulation in patients reported so far (3)(4)(5)(6)(7)(8)(9). This is the first report of a pediatric patient with syndromic immunodeficiency, autoinflammation, hemophagocytic lymphohistiocytosis, and malignant lymphoproliferation in whom a novel, heterozygous p.Cys81Tyr mutation in the CDC42 gene was found.…”

The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype

“…In conclusion, we show that the recurrent postzygotic missense variant p.Glu47Lys in RHOA causes a specific human phenotype characterized by hypopigmentation of the skin, dental anomalies, body asymmetry, and length discrepancy of limbs, as well as brain MRI anomalies. In our study, all four individuals carry the identified variation as a somatic mosaic variant, suggesting that, in contrast to, for example, other Rho family members like RAC1, RAC3, and CDC42 (Costain et al, ; Martinelli et al, ; Reijnders et al, ), nonmosaic mutations in RHOA might be lethal, and we speculate that the distinct phenotype observed in our patients is caused by disruption of RHOA interaction with its effectors.…”

“…for example, other Rho family members like RAC1, RAC3, and CDC42 (Costain et al, 2019;Martinelli et al, 2018;Reijnders et al, 2017), nonmosaic mutations in RHOA might be lethal, and we speculate that the distinct phenotype observed in our patients is caused by disruption of RHOA interaction with its effectors.…”

A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome

“…Small GTPases of the Rho family have recently been increasingly associated to inflammatory diseases and complex phenotypes in humans [5][6][7][8] , and thus represent potential candidates in such signaling dysfunctions. Previous findings classify psoriasiform manifestations in the group of AID.…”