The Growing Spectrum of Human Diseases Caused by Inherited CDC42 Mutations
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COMMENTARY
The Growing Spectrum of Human Diseases Caused by Inherited CDC42 Mutations Helen C. Su 1 & Jordan S. Orange 2
# This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020
Abstract Several recent studies provide valuable new information that expands the spectrum of human disease associated with mutations in CDC42.
CDC42, an intracellular member of the Rho-family GTPases, is a key regulator of cell polarity that is highly conserved among eukaryotes (reviewed in [1]). By regulating the assembly of actin cytoskeletal structures in a temporal-spatial manner, CDC42, along with RAC and RHO A, controls cell shape and cell movement. In this way, CDC42 plays an important role in migration and directed functions, processes that are integral for embryonic development, hematopoiesis, or immune system function. CDC42 also influences other functions such as cell growth and proliferation through effects on multiple downstream cell signaling pathways, via actin-based platforms and/or direct interactions of CDC42 with other effectors. As a GTPase, CDC42 functions as an intracellular molecular switch. It cycles between two forms—an active form when bound to GTP and an inactive form when bound to GDP—subject to complex regulation by GTPase activation proteins (GAPs), guanosine exchange factors (GEFs), and guanosine dissociation inhibitors (GDIs). When activated, CDC42 undergoes a conformational change that enables it to associate with membranes and to interact with effector molecules, which in turn undergo their own conformational changes to exert downstream biochemical functions.
* Helen C. Su [email protected] 1
Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
2
Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York-Presbyterian Morgan Stanley Children’s Hospital, Columbia University, New York, NY 10032, USA
To understand how CDC42 biologically functions, much work had been done using cell lines that express dominantly negative or constitutively active mutants. However, these mutants can exert non-specific effects by binding guanine nucleotide exchange factors that not only affect CDC42 but also other Rho-family GTPases. Physiological studies using mice rendered genetically deficient in Cdc42 have been limited by embryonic lethality. However, mice rendered conditionally deficient for Cdc42 revealed its requirement for proper tissue morphogenesis and functioning, including effects on the cardiac, nervous, hematopoietic, and immune systems. Clues provided by studies in mutant mice were soon followed by the identification of humans with inherited CDC42 mutations. From 2015 onward, the first patients were reported to have a de novo heterozygous missense mutation in CDC42 at p.Tyr64Cys, associated with a constellation of features termed as Takenouchi-Kosaki syndrome, which includes dysmorph
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