This report describes a disease or diseases recently associated with a specific variant in the human CDC42 gene, CDC42:p.Arg186Cys . Heterozygosity for the R186C variant is observed to result in disease. CDC42 encodes a small GTPase of the Rho-subfamily; Rho GTPases participate in the regulation of a wide variety of signal transduction pathways and play a key role in cytoskeleton organization. Multiple different missense mutations of CDC42 have been implicated in the disease Takenouchi-Kosaki syndrome (MIM:616737). However the phenotypes observed in carriers of the CDC42:p.Arg186Cys variant differ significantly from those of Takenouchi-Kosaki syndrome.
CDC42 is orthologous to the Drosophila gene Cdc42, for which classical loss-of-function alleles, RNAi-targeting constructs, alleles caused by insertional mutagenesis, and overexpression constructs have been generated. The human Hsap\CDC42 gene has been introduced into flies, but has not been characterized in the context of this disease model.
A mutation analogous to CDC42:p.Arg186Cys was introduced into the Drosophila Cdc42 gene in a transgenic UAS construct. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R186C in the fly Cdc42 (corresponds to R186C in the human CDC42 gene). When the R186C Cdc42 transgene is expressed in hemocytes, normal hematopoietic cell migration is disrupted. This is observed without modification of the endogenous Cdc42 genes, thus appears to be a dominant effect.
[updated Aug. 2020 by FlyBase; FBrf0222196]
Several recent studies describe a syndrome termed NOCARH (neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and hemophagocytic lymphohistiocytosis) associated specifically with the p.Arg186Cys variant of CDC42. An additional study describes siblings with congenital pancytopenia and myelofibrosis associated with the same variant (Su and Orange, 2020; pubmed:32417998).
Recently, there have been multiple reports of patients with heterozygous missense mutations in CDC42 at p.Arg186Cys that present with symptoms that differ from Takenouchi-Kosaki syndrome, a disease previously associated with CDC42 (Su and Orange, 2020; pubmed:32417998).
CDC42 encodes a small GTPase of the Rho-subfamily, which regulates signaling pathways that control diverse cellular functions including cell morphology, migration, endocytosis and cell cycle progression. [Gene Cards, CDC42; 2020.08.29]
When activated, CDC42 undergoes a conformational change that enables it to associate with membranes and to interact with effector molecules (Su and Orange, 2020; pubmed:32417998).
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human CDC42 (reciprocal best hit; 1 Drosophila to 1 human). Dmel\Cdc42 shares 93% identity and 95% similarity with the human gene.
