Alternative titles; symbols
HGNC Approved Gene Symbol: CDC42
SNOMEDCT: 1172685001;
Cytogenetic location: 1p36.12 Genomic coordinates (GRCh38): 1:22,052,709-22,101,360 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.12 | Takenouchi-Kosaki syndrome | 616737 | Autosomal dominant | 3 |
CDC42 is a Ras (see 190020)-related GTP-binding protein. It is implicated in a variety of biologic activities, including establishment of cell polarity in yeast, regulation of cell morphology, motility, and cell cycle progression in mammalian cells, and induction of malignant transformation (summary by Wu et al., 2000).
Shinjo et al. (1990) isolated cDNA clones that code for cdc42, a low molecular weight GTP-binding protein originally designated G(p) and also called G25K, from a human placenta library. The predicted amino acid sequence of the protein was very similar to those of various members of the RAS superfamily of low molecular weight GTP-binding proteins, including NRAS, KRAS, HRAS, and the RHO proteins. The highest degree of sequence identity (80%) was found with the Saccharomyces cerevisiae cell division cycle protein CDC42. The human placental gene complemented a cdc42 mutation in S. cerevisiae. Munemitsu et al. (1990) presented further evidence that G25K is the human homolog of the CDC42 gene product.
Marks and Kwiatkowski (1996) identified 2 isoforms of mouse Cdc42. They demonstrated that the 2 murine isoforms arise from a single gene by alternative splicing. Although one is expressed in a wide variety of tissues, the second isoform appeared to be expressed exclusively in brain.
Erickson et al. (1996) used cell fractionation and immunofluorescence to show that cdc42 is localized to the Golgi apparatus of mammalian cells. It colocalizes with the nonclathrin coat proteins ARF3 (103190) and COPB (600959) and its Golgi localization is disrupted by the drug brefeldin A. Based on their findings, Erickson et al. (1996) suggested that cdc42 may be involved in the delivery of newly synthesized proteins and lipids to the plasma membrane and that the GTP-binding/GTPase cycle may dictate its subcellular localization.
By screening rat brain cytosol for proteins that interacted with Ras-related GTPases, or p21 proteins, of the Rho (RHOA; 165390) subfamily, Manser et al. (1994) identified 3 proteins, designated PAKs (see PAK1; 602590) that interacted with the GTP-bound forms of human CDC42 and RAC1 (602048), but not RHOA. Brown et al. (1996) found that activity of human PAK1 was induced by coexpression with RAC1 or CDC42.
Zheng et al. (1996) reported that the FGD1 protein (305400) acts as a cdc42-specific GDP-GTP exchange factor. Cells expressing a fragment of the FGD1 protein encompassing the pleckstrin and Dbl homology domains activated 2 elements downstream of cdc42, namely, Jun kinase (165160) and p70 S6 kinase.
Manser et al. (1993) identified ACK1 (606994) as a binding partner and inhibitor of the GTP-bound form of CDC42. Interaction between GTP-CDC42 and ACK1 inhibited both the intrinsic and GAP-stimulated GTPase activity of CDC42.
CDC42 can regulate the actin cytoskeleton through activation of WASP family members (see 301000). Activation relieves an autoinhibitory contact between the GTPase-binding domain and the C-terminal region of WASP proteins. Kim et al. (2000) reported the autoinhibited structure of the GTPase-binding domain of WASP, which can be induced by the C-terminal region or by organic cosolvents. In the autoinhibited complex, intramolecular interactions with the GTPase-binding domain occlude residues of the C terminus that regulate the Arp2/3 actin-nucleating complex (see 604221). Binding of CDC42 to the GTPase-binding domain causes a dramatic conformational change, resulting in disruption of the hydrophobic core and release of the C terminus, enabling its interaction with the actin regulatory machinery.
Wu et al. (2000) identified a CDC42 mutant, Cdc42F28L, that binds GTP in the absence of a guanine nucleotide exchange factor, but still hydrolyzes GTP with a turnover number identical to that for wildtype CDC42. Expression of this mutant in fibroblasts causes cellular transformation, mimicking many of the characteristics of cells transformed by the DBL oncoprotein (311030), a known guanine nucleotide exchange factor for CDC42. Wu et al. (2000) searched for new CDC42 targets in an effort to understand how CDC42 mediates cellular transformation. They identified the gamma-subunit of the coatomer complex (gamma-COP; 604355) as a specific binding partner for activated CDC42. The binding of CDC42 to gamma-COP is essential for a transforming signal distinct from those elicited by Ras.
Dendritic cells (DCs) developmentally regulate antigen uptake by controlling their endocytic capacity. Immature DCs actively internalize antigen. Mature DCs, however, are poorly endocytic, functioning instead to present antigens to T cells. Garrett et al. (2000) found that endocytic downregulation reflects a decrease in endocytic activity controlled by RHO family GTPases, especially CDC42. Blocking CDC42 function by toxin B treatment or injection of dominant-negative inhibitors of CDC42 abrogated endocytosis in immature DCs. In mature DCs, injection of constitutively active CDC42 or microbial delivery of a CDC42 nucleotide exchange factor reactivated endocytosis. DCs regulated endogenous levels of CDC42-GTP with activated CDC42 detectable only in immature cells. Garrett et al. (2000) concluded that DCs developmentally regulate endocytosis at least in part by controlling levels of activated CDC42.
Using Madin Darby canine kidney (MDCK) cells expressing Cdc42 mutants defective in nucleotide binding or hydrolysis, Musch et al. (2001) showed that Cdc42 differentially regulated the exit of apical and basolateral proteins from the trans-Golgi network (TGN). GTPase-deficient Cdc42 accelerated the exit of an apical marker from the TGN and inhibited the release of basolateral proteins. Basolateral protein transport by Cdc42 with an activating mutation was accompanied by changes in the organization of the actin cytoskeleton.
Sin et al. (2002) used in vivo time-lapse imaging of optic tectal cells in Xenopus laevis tadpoles to demonstrate that enhanced visual activity driven by a light stimulus promotes dendritic arbor growth. The stimulus-induced dendritic arbor growth requires glutamate receptor (see 138249)-mediated synaptic transmission, decreased RhoA (165390) activity, and increased RAC and CDC42 activity. Sin et al. (2002) concluded that their results delineated a role for Rho GTPases in the structural plasticity driven by visual stimulation in vivo.
Morphologic changes in dendritic spines are believed to be caused by dynamic regulation of actin polymerization. Irie and Yamaguchi (2002) found that the EphB2 receptor tyrosine kinase (600997) physically associates with the guanine nucleotide exchange factor intersectin-1 (602442) in cooperation with the actin-regulating protein N-WASP (605056), which in turn activates Cdc42 and spine morphogenesis.
In higher eukaryotes, the small GTPase CDC42, acting through a PAR6-atypical protein kinase C (see PKC-zeta, 176982) complex, is required to establish cellular asymmetry during epithelial morphogenesis, asymmetric cell division, and directed cell migration. Etienne-Manneville and Hall (2003) used primary rat astrocytes in a cell migration assay to demonstrate that PAR6-PKC-zeta interacts directly with and regulates glycogen synthase kinase-3-beta (GSK3-beta; 605004) to promote polarization of the centrosome and to control the direction of cell protrusion. CDC42-dependent phosphorylation of GSK3-beta occurs specifically at the leading edge of migrating cells, and induces the interaction of APC (611731) protein with the plus ends of microtubules. The association of APC with microtubules is essential for cell polarization. Etienne-Manneville and Hall (2003) concluded that CDC42 regulates cell polarity through the spatial regulation of GSK3-beta and APC.
Wu et al. (2003) presented evidence that activation of CDC42 protects EGF receptor (EGFR; 131550) from the negative regulatory activity of CBL (165360), a ubiquitin ligase.
Yasuda et al. (2004) demonstrated that Cdc42 and mDia3 (DIAPH2; 300108) regulate microtubule attachment to kinetochores.
Nalbant et al. (2004) reported the development of a biosensor capable of visualizing the changing activation of endogenous unlabeled Cdc42 in living cells. With the use of a dye that reports protein interactions, the biosensor revealed localized activation in the trans-Golgi apparatus, microtubule-dependent Cdc42 activation at the cell periphery, and activation kinetics precisely coordinated with cell extension and retraction.
By electroporating genes into chicken presomitic mesenchymal cells, Nakaya et al. (2004) demonstrated that Cdc42 and Rac1 play different roles in mesenchymal-epithelial transition. Different levels of Cdc42 appeared to affect the binary decision between epithelial and mesenchymal states. Proper levels of Rac1 were also necessary for somitic epithelialization, since cells with either activated or inhibited Rac1 failed to undergo correct epithelialization.
Using functional and proteomic screens to identify regulators of Cdc42, Wells et al. (2006) identified a network of proteins that centered on Rich1 (ARHGAP17; 608293) and organized apical polarity in canine kidney epithelial cells. Rich1 bound the coiled-coil domain of Amot (300410) and was thereby targeted to a complex at tight junctions containing the PDZ domain-containing proteins Pals1 (MPP5; 606958), Patj (INADL; 603199), and Par3 (PARD3; 606745). Regulation of Cdc42 by Rich1 was required for maintenance of tight junctions. The coiled-coil domain of Amot was required for its localization to apical membranes and for Amot to relocalize Pals1 and Par3 to internal puncta. Wells et al. (2006) proposed that RICH1 and AMOT maintain tight junction integrity by coordinated regulation of CDC42 and by linking specific components of the tight junction to intracellular protein trafficking.
Formation of the apical surface and lumen is a fundamental step in epithelial organ development. Martin-Belmonte et al. (2007) showed that Pten (601728) localized to the apical plasma membrane during epithelial morphogenesis to mediate enrichment of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) at this domain during cyst development in a 3-dimensional Madin-Darby canine kidney cell system. Ectopic PtdIns(4,5)P2 at the basolateral surface caused apical proteins to relocalize to the basolateral surface. Annexin-2 (ANX2; 151740) bound PtdIns(4,5)P2 and was recruited to the apical surface. Anx2 bound Cdc42 and recruited it to the apical surface, and Cdc42 in turn recruited the Par6 (607484)/atypical protein kinase C (aPKC; see 176982) complex to the apical surface. Loss of function of Pten, Anx2, Cdc42, or aPKC prevented normal development of the apical surface and lumen. Martin-Belmonte et al. (2007) concluded that PTEN, PtdIns(4,5)P2, ANX2, CDC42, and aPKC control apical plasma membrane and lumen formation.
Hamann et al. (2007) found that both ASEF1 and ASEF2 were guanine nucleotide exchange factors (GEFs) for CDC42, but not for RAC1 or RHOA. ASEF2 required the lipid-modified form of CDC42. Using deletion mutants, Hamann et al. (2007) showed that the tandem N-terminal ABR and SH3 domain (ABRSH3) of the ASEF proteins was required to bind the armadillo repeat region of APC. ABRSH3 also functioned in an autoinhibitory reaction by binding the C-terminal tails of ASEF1 and ASEF2 and inhibiting their GEF activities. Deletion of ABRSH3 or coexpression of the APC armadillo repeat sequence with full-length ASEF2 stimulated filopodia formation in transfected HeLa cells. Hamann et al. (2007) concluded that activation of ASEF1 and ASEF2 involves binding of APC to ABRSH3, which disrupts the autoinhibitory interaction of ABRSH3 with the ASEF C-terminal tail and allows GDP/GTP exchange on CDC42.
Kawasaki et al. (2007) found that ASEF2 was a GEF for both CDC42 and RAC1 in MDCK and HeLa cells. Overexpression of ASEF2 increased membrane ruffling and CDC42-mediated filopodia formation in HeLa cells.
Shen et al. (2008) showed that Nudel (NDEL1; 607538) colocalized with Cdc42gap (ARHGAP1; 602732) at the leading edge of migrating NIH3T3 mouse fibroblasts. This localization of Nudel required its phosphorylation by Erk1 (MAPK3; 601795)/Erk2 (MAPK1; 176948). Shen et al. (2008) found that Nudel competed with Cdc42 for binding Cdc42gap. Consequently, Nudel inhibited Cdc42gap-mediated inactivation of Cdc42 in a dose-dependent manner. Depletion of Nudel by RNA interference or overexpression of a nonphosphorylatable Nudel mutant abolished Cdc42 activation and cell migration. Shen et al. (2008) concluded that NUDEL facilitates cell migration by sequestering CDC42GAP at the leading edge to stabilize active CDC42 in response to extracellular stimuli.
Kang et al. (2008) performed a global characterization of rat neural palmitoyl proteomes and identified most of the known neural palmitoyl proteins, 68 in total, plus more than 200 novel palmitoyl protein candidates, with further testing confirming palmitoylation for 21 of these candidates. The novel palmitoyl proteins included neurotransmitter receptors, transporters, adhesion molecules, scaffolding proteins, as well as SNAREs and other vesicular trafficking proteins. Of particular interest was the finding of palmitoylation for a brain-specific Cdc42 splice variant. The palmitoylated Cdc42 isoform (Cdc42-palm) differs from the canonical, prenylated form (Cdc42-prenyl), with regard to both localization and function: Cdc42-palm concentrates in dendritic spines and has a special role in inducing these postsynaptic structures. Furthermore, assessing palmitoylation dynamics in drug-induced activity models identified rapidly induced changes for Cdc42 as well as for other synaptic palmitoyl proteins, suggesting that palmitoylation may participate broadly in the activity-driven changes that shape synapse morphology and brain function.
Machacek et al. (2009) examined GTPase coordination in mouse embryonic fibroblasts both through simultaneous visualization of 2 GTPase biosensors and using a 'computational multiplexing' approach capable of defining the relationships between multiple protein activities visualized in separate experiments. They found that RhoA (165390) is activated at the cell edge synchronous with edge advancement, whereas Cdc42 and Rac1 are activated 2 microns behind the edge with a delay of 40 seconds. This indicates that Rac1 and RhoA operate antagonistically through spatial separation and precise timing, and that RhoA has a role in the initial events of protrusion, whereas Rac1 and Cdc42 activate pathways implicated in reinforcement and stabilization of newly expanded protrusions.
Frank et al. (2009) found that Cdc42 was involved in a signaling complex that modulated presynaptic Cav2.1 (CACNA1A; 601011) calcium channels in the Drosophila neuromuscular junction. This signaling system involved the Rho-type GEF ephexin (NGEF; 605991), which appeared to act with Cdc42 to activate the Eph receptor (see EPHA1; 179610) for modulation of Cav2.1 channel activity.
Murakoshi et al. (2011) used 2-photon fluorescence lifetime imaging microscopy to monitor the activity of 2 Rho GTPases, RhoA and Cdc42, in single dendritic spines undergoing structural plasticity associated with long-term potentiation in CA1 pyramidal neurons in cultured slices of rat hippocampus. When long-term volume increase was induced in a single spine using 2-photon glutamate uncaging, RhoA and Cdc42 were rapidly activated in the stimulated spine. These activities decayed over about 5 minutes, and were then followed by a phase of persistent activation lasting more than half an hour. Although active RhoA and Cdc42 were similarly mobile, their activity patterns were different. RhoA activation diffused out of the stimulated spine and spread over about 5 microns along the dendrite. In contrast, Cdc42 activation was restricted to the stimulated spine, and exhibited a steep gradient at the spine necks. Inhibition of the Rho-Rock pathway preferentially inhibited the initial spine growth, whereas the inhibition of the Cdc42-Pak pathway blocked the maintenance of sustained structural plasticity. RhoA and Cdc42 activation depended on calcium ion/calmodulin-dependent kinase (CaMKII). Thus, Murakoshi et al. (2011) concluded that RhoA and Cdc42 relay transient CaMKII activation to synapse-specific, long-term signaling required for spine structural plasticity.
Using synthetic derivatives of the enteropathogenic Escherichia coli guanine-nucleotide exchange factor Map, Orchard et al. (2012) found that CDC42 GTPase signal transduction was controlled by interaction between Map and the PDZ domains of EBP50 (SLC9A3R1; 604990) and the induction of clusters of actin-rich membrane protrusions.
Keestra et al. (2013) demonstrated that NOD1 (605980) senses cytosolic microbial products by monitoring the activation state of small Rho GTPases. Activation of RAC1 (602048) and CDC42 by bacterial delivery or ectopic expression of SopE, a virulence factor of the enteric pathogen Salmonella, triggered the NOD1 signaling pathway with consequent RIP2 (603455)-mediated induction of NF-kappa-B (see 164011)-dependent inflammatory responses. Similarly, activation of the NOD1 signaling pathway by peptidoglycan required RAC1 activity. Furthermore, Keestra et al. (2013) showed that constitutively active forms of RAC1, CDC42, and RHOA (165390) activated the NOD1 signaling pathway.
Florian et al. (2013) reported an unexpected shift from canonical to noncanonical Wnt signaling in mice due to elevated expression of Wnt5a (164975) in aged hematopoietic stem cells (HSCs), which causes stem cell aging. Wnt5a treatment of young HSCs induced aging-associated stem cell apolarity, reduction of regenerative capacity, and an aging-like myeloid-lymphoid differentiation skewing via activation of the small Rho GTPase Cdc42. Conversely, Wnt5a haploinsufficiency attenuated HSC aging, whereas stem cell-intrinsic reduction of Wnt5a expression resulted in functionally rejuvenated aged HSCs. Florian et al. (2013) concluded that the data demonstrated a critical role for stem cell-intrinsic noncanonical Wnt5a signaling in HSC aging.
Park et al. (2015) showed that the coat protein I complex (COPI; see 601924) sorts anterograde cargoes into tubules that connect the Golgi cisternae in human cells. Moreover, the small GTPase CDC42 regulates bidirectional Golgi transport by targeting the dual functions of COPI in cargo sorting and carrier formation. CDC42 also directly imparts membrane curvature to promote COPI tubule formation. Park et al. (2015) concluded that their findings further revealed that COPI tubular transport complements cisternal maturation in explaining how anterograde Golgi transport is achieved, and that bidirectional COPI transport is modulated by environmental cues through CDC42.
By transfecting MDCK canine kidney cell with wildtype or mutant human constructs, and by knockdown of endogenous MDCK proteins, Hayase et al. (2013) studied development of apical-basolateral polarity. Their results suggested that cytoplasmic MORG1 (WDR83; 616850) interacted directly with PAR6 (607484) and mediated apical translocation of a dimer made up of PAR6 and an atypical PKC (aPKC, e.g., PRKCI, 600539). MORG1 also interacted with the apical transmembrane protein CRB3 (609737) and facilitated binding between PAR6 and CRB3, thereby anchoring the PAR6-aPKC dimer to the apical membrane. The small GTPase CDC42 displaced MORG1 from the complex at the apical membrane and strengthened the association between PAR6 and CRB3. Knockdown of any complex component interfered with development of polarity in MDCK cells; however, overexpression of a CRB3-aPKC construct reversed the polarity defect in MORG1-deficient MDCK cells and restored apical identity.
In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle. This implies some asymmetry between the 2 sides of the spindle. Akera et al. (2017) found that CDC42 signaling from the cell cortex regulated microtubule tyrosination to induce spindle asymmetry and that non-Mendelian segregation depended on this asymmetry. Cortical CDC42 depends on polarization directed by chromosomes, which are positioned near the cortex to allow the asymmetric cell division. Thus, Akera et al. (2017) selfish meiotic drivers exploit the asymmetry inherent in female meiosis to bias their transmission.
Hedrick et al. (2016) described a 3-molecule model of structural long-term potentiation of murine dendritic spines, implicating the localized, coincident activation of Rac1, RhoA, and Cdc42 as a causal signal of structural long-term potentiation. This model posited that complete tripartite signal overlap in spines confers structural long-term potentiation, but that partial overlap primes spines for structural plasticity. By monitoring the spatiotemporal activation patterns of these GTPases during structural long-term potentiation, Hedrick et al. (2016) found that such spatiotemporal signal complementation simultaneously explains 3 integral features of plasticity: the facilitation of plasticity by BDNF (113505), the postsynaptic source of which activates Cdc42 and Rac1, but not RhoA; heterosynaptic facilitation of structural long-term potentiation, which is conveyed by diffusive Rac1 and RhoA activity; and input specificity, which is afforded by spine-restricted Cdc42 activity.
Nicole et al. (1999) determined the organization of the CDC42 gene and found that the gene encodes the placental and brain isoforms generated by alternative splicing.
Moats-Staats and Stiles (1995) showed that the 5-prime end of another gene, called BB1 by them, overlaps the 3-prime end of G25K.
Crystal Structure
Through a structural analysis of DOCK9 (607325)-CDC42 complexes, Yang et al. (2009) identified a nucleotide sensor within the alpha-10 helix of the DHR2 domain that contributes to release of guanine diphosphate (GDP) and then to discharge of the activated GTP-bound Cdc42. Magnesium exclusion, a critical factor in promoting GDP release, is mediated by a conserved valine residue within this sensor, whereas binding of GTP-magnesium ion to the nucleotide-free complex results in magnesium-inducing displacement of the sensor to stimulate discharge of Cdc42-GTP. Yang et al. (2009) concluded that their studies identified an unusual mechanism of GDP release and defined the complete guanine nucleotide exchange factor catalytic cycle from GDP dissociation followed by GTP binding and discharge of the activated GTPase.
Using SSCP analysis of a mouse backcross panel, Marks and Kwiatkowski (1996) demonstrated that the gene encoding cdc42 is localized to the distal portion of mouse chromosome 4 between Ephb2 proximally and Cappb (601572) distally. The human homologs of both of the 2 flanking genes were mapped to human chromosome 1p36.1 by Barron-Casella et al. (1995), thus indicating that this is the likely site of the human CDC42 gene. The CDC42 gene was mapped to the 1p36-p35 region by radiation hybrid analysis (Schuler et al., 1996; Jensen et al., 1997; Deloukas et al., 1998).
Nicole et al. (1999) demonstrated a CDC42-like transcript on chromosome 4 that does not contain introns and is similar to the placental isoform, suggesting that it is a processed pseudogene.
Nicole et al. (1999) excluded the CDC42 gene as the site of mutation in the Schwartz-Jampel syndrome type 1 (255800).
Takenouchi et al. (2015) and Takenouchi et al. (2016) each reported a patient with macrothrombocytopenia, lymphedema, developmental delay, and similar distinctive facial features, known as Takenouchi-Kosaki syndrome (TKS; 616737). Both patients were heterozygous for the same de novo mutation in the CDC42 gene (116952.0001).
In 15 patients from 13 unrelated families with a heterogeneous developmental disorder consistent with TKS, Martinelli et al. (2018) identified 9 different heterozygous missense mutations in the CDC42 gene (see, e.g., 116952.0001-116952.0006). The mutations occurred de novo in 12 unrelated patients; there was 1 family (family 30153) in which 3 affected individuals carried the same mutation. The mutations in most patients were identified by whole-exome sequencing; some mutations were identified by direct sequencing of the CDC42 gene. None of the mutations were found in the ExAC/gnomAD database, and all were predicted to be pathogenic according to ACMG criteria. Based on molecular modeling, predicted functional impact, and in vitro functional studies, the mutations were categorized into 3 main groups, all of which were determined to be pathogenic (see GENOTYPE/PHENOTYPE CORRELATIONS).
Based on molecular modeling, predicted functional impact, and in vitro functional studies, the mutations identified by Martinelli et al. (2018) were categorized into 3 main groups. Group I mutations (Y64C; R66G, 116952.0002; and R68Q) occurred in the switch II domain, which mediates CDC42 binding to effectors and regulators, and were predicted to interfere with the catalytic activity of the GTPase and/or its capability to transduce signaling. Group I mutations were associated with a syndromic form of thrombocytopenia. Group II mutations (C81F, 116952.0003; S83P, 116952.0004; and A159V) were located within or close to the nucleotide-binding pocket, and were predicted to promote fast GDP/GTP cycling, favoring a hyperactive GTP-bound state. Group II mutations were associated with a variable developmental disorder characterized by striking dysmorphic features resembling a RASopathy. Group III mutations (I21T, 116952.0005; Y23C; and E171K, 116952.0006), located in residues predicted to disrupt interactions with effectors containing a CRIB (Cdc42, Rac interactive binding) motif, were associated with a milder phenotype resembling Noonan syndrome. In vitro studies of selected mutations using recombinant proteins showed variable effects on CDC42 function, including altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors. Group I mutations had defective interaction with tested partner proteins, group II mutations showed variable hyperactive behavior, and group III mutations showed perturbed binding to effectors. In addition, a wound healing assay indicated that the mutations resulted in dysregulated and disturbed cell polarization and proliferation. One specific mutation (E171K), which affects only 1 of the 2 CDC42 isoforms and specifically impaired binding to WASP (300392), resulted in an overall milder clinical phenotype that phenocopied Noonan syndrome. Studies in C. elegans showed that the mutations caused variable disruption of developmental processes, with some mutations acting as a gain of function and others acting as hypomorphs. In general, the group II mutations upregulated multiple signaling pathways. Overall, the findings indicated that CDC42 functions in a large array of developmental processes.
Wu et al. (2006) stated that constitutive knockout of Cdc42 in mice results in death around implantation. In order to examine the role of Cdc42 in the differentiation of skin stem cells into hair follicles, they targeted Cdc42 deletion to keratinocytes. Mutant mice were born without obvious defects but showed impaired hair formation and growth retardation. Within 4 weeks, all hairs were lost and did not grow again in older animals. In the absence of Cdc42, degradation of beta-catenin (CTNNB1; 116806) increased corresponding to decreased phosphorylation of Gsk3-beta and increased phosphorylation of axin (603816), which is required for binding of beta-catenin to the degradation machinery. Wu et al. (2006) concluded that Cdc42 regulation of beta-catenin turnover is required for terminal differentiation of hair follicle progenitor cells.
By targeted deletion of Cdc42 in telencephalic neural progenitors in mouse embryos, Chen et al. (2006) found that Cdc42 was essential for establishment of apical-basal polarity of the telencephalic neuroepithelium, a necessity for expansion and bifurcation of cerebral hemispheres.
Pleines et al. (2010) found that conditional knockout of Cdc42 in mice results in mild thrombocytopenia and increased platelet size (i.e., macrothrombocytopenia).
In 2 unrelated females, one of Japanese-Iranian descent and the other of Japanese descent, with a syndrome of macrothrombocytopenia, developmental delay, and distinctive facial features (TKS; 616737), Takenouchi et al. (2015) and Takenouchi et al. (2016) identified a heterozygous c.191A-G transition (c.191A-G, NM_001039802) in exon 3 of the CDC42 gene, resulting in a tyrosine-to-cystine substitution at codon 64 (Y64C). The mutation was confirmed in both patients by Sanger sequencing and was not identified in either parent.
In a 15-year-old girl (patient LR17-420) with TKS, Martinelli et al. (2018) identified a de novo heterozygous Y64C mutation in the CDC42 gene. The mutation, which was found by whole-exome sequencing, was not found in the ExAC/gnomAD database and met the ACMG criteria for pathogenicity.
In 2 unrelated patients (LR14-352 and PCGC 1-04248) with Takenouchi-Kosaki syndrome (TKS; 616737), Martinelli et al. (2018) identified a de novo heterozygous c.196A-G transition (c.196A-G, NM_001791.3) in exon 3 of the CDC42 gene, resulting in an arg66-to-gly (R66G) substitution at a conserved residue in the switch II domain. The mutation, which was found by whole-exome sequencing, was not found in the ExAC/gnomAD database and met the ACMG criteria for pathogenicity.
In a 4-year-old boy (LR17-032), born of unrelated parents, with Takenouchi-Kosaki syndrome (TKS; 616737), Martinelli et al. (2018) identified a de novo heterozygous c.242G-T transversion (c.242G-T, NM_001791.3) in exon 3 of the CDC42 gene, resulting in a cys81-to-phe (C81F) substitution at a conserved residue in the beta-4 domain. The mutation, which was found by whole-exome sequencing, was not found in the ExAC/gnomAD database and met the ACMG criteria for pathogenicity.
In a boy (LR10-046), conceived by in vitro fertilization, with Takenouchi-Kosaki syndrome (TKS; 616737), Martinelli et al. (2018) identified a de novo heterozygous c.247T-C transition (c.247T-C, NM_001791.3) in exon 3 of the CDC42 gene, resulting in a ser83-to-pro (S83P) substitution in the beta-4 domain. The mutation, which was found by whole-exome sequencing, was not found in the ExAC/gnomAD database and met the ACMG criteria for pathogenicity.
In a patient (LR16-483) with Takenouchi-Kosaki syndrome (TKS; 616737), Martinelli et al. (2018) identified a de novo heterozygous c.62T-C transition (c.62T-C, NM_001791.3) in exon 1 of the CDC42 gene, resulting in an ile21-to-thr (I21T) substitution at a conserved residue in the alpha-1 domain. The mutation, which was found by whole-exome sequencing, was not found in the ExAC/gnomAD database and met the ACMG criteria for pathogenicity.
In 3 members of a family (family 30153) with Takenouchi-Kosaki syndrome (TKS; 616737), Martinelli et al. (2018) identified a heterozygous c.511G-A transition (c.511G-A, NM_001791.3) in exon 5 of the CDC42 gene, resulting in a glu171-to-lys (E171K) substitution at a conserved residue in the CBR domain. An unrelated patient (M060721) with a similar disorder carried this mutation in the de novo state. The mutation only affected transcript variant 1 and isoform 1 of CDC42. The mutation was not found in the ExAC/gnomAD database and met the ACMG criteria for pathogenicity.
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