Abstract
Rho family guanosine triphosphatases (GTPases) regulate cellular signaling and cytoskeletal dynamics, playing a pivotal role in cell adhesion, migration, and cell cycle progression. The Rac subfamily of Rho GTPases consists of three highly homologous proteins, Rac 1–3. The proper function of Rac1 and Rac3, and their correct interaction with guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) are crucial for neural development. Pathogenic variants affecting these delicate biological processes are implicated in different medical conditions in humans, primarily neurodevelopmental disorders (NDDs). In addition to a direct deleterious effect produced by genetic variants in the RAC genes, a dysregulated GTPase activity resulting from an abnormal function of GEFs and GAPs has been involved in the pathogenesis of distinctive emerging conditions. In this study, we reviewed the current pertinent literature on Rac-related disorders with a primary neurological involvement, providing an overview of the current knowledge on the pathophysiological mechanisms involved in the neuro-RACopathies.
Highlights
Twenty small Rho family guanosine triphosphatases (GTPases) have been identified in humans, classified in eight major subfamilies based on structural and biological properties: Rho, Rac, Cdc42, RhoU/RhoV, Rnd, RhoD/R, hoF, RhoBTB, and RhoH subfamilies [1,2]
The RAC subfamily is part of the typical group of Rho GTPases, together with Rhoand CDC42-subfamilies, meaning that the members of this subfamily undergo classical GTPase cycle [5]. They act as a molecular switch, cycling between GTP-bound and guanosine diphosphate (GDP)-bound states, in a cycle which is strictly regulated by three groups of regulatory proteins with a very specific functional role: Cells 2021, 10, 3395 and guanosine diphosphate (GDP)-bound states, in a cycle which is strictly regulated by three groups of regulatory proteins with a very specific functional GroTleP:asGe-TaPctaivsea-tainctgivpartointeginsp(rGotAeiPnss), g(GuaAnPins)e, nguuclaenoitnidee-nduiscsloecoitaidtieo-ndiinsshoibciiatotirosn(GiDnhIsi)b,iatonrds g(GuaDnIisn),eannudclgeuoatindineeexncuhcalenogteidfeacetxocrhs a(GngEeFfsa)c[t6o]r.sG(DGEP/FsG)T[6P].bGinDdPin/Gg TanPdbiGnTdPinhgyadnrdolGysTiPs ahryedmroeldyisaisteadrebymtehdeiahtiegdhlbyyctohnesherigvhedlyGcodnosmeraviend(FGigduorme 1a)i.n (Figure 1)
The abnormal modulation or disruption of their function is implicated in the pathogenesis of distinctive human conditions with abnormal brain development and neurological impairment, collectively definable as neuroRACopathies
Summary
Twenty small Rho family guanosine triphosphatases (GTPases) have been identified in humans, classified in eight major subfamilies based on structural and biological properties: Rho-, Rac-, Cdc42-, RhoU/RhoV-, Rnd-, RhoD/R-, hoF-, RhoBTB-, and RhoH subfamilies [1,2]. The RAC subfamily is part of the typical group of Rho GTPases, together with Rhoand CDC42-subfamilies, meaning that the members of this subfamily undergo classical GTPase cycle [5] They act as a molecular switch, cycling between GTP-bound (active) and guanosine diphosphate (GDP)-bound (inactive) states, in a cycle which is strictly regulated by three groups of regulatory proteins with a very specific functional role: Cells 2021, 10, 3395. In addition to specific regulators and effectors, Rac proteins are predicted to interact with several proteins with a relevant biological role Some of these interactors are already associated with a human condition, with or without a primary neurological involvement, according to the Online Mendelian Inheritance in Man (OMIM) database (https://www.omim.org, accessed on 19 October 2021) (Figure 3). IInn tthhiis review, wweepprroovvidideeananovoevrevriveiwewofotfhethceurcruernrteknnt okwnloewdgleedogne tohne pthaethpoapthhyos-piohlyosgioiclaolgmicaecl hmaencihsmansisinmvsoilnvevdolivneRdAinCR-rAelCat-eredladtiesdorddiesrosrdweirtshwneituhrondeuevroedloepvmeleonptmalemntaanlmifaenstiafetisotantsio(nnseu(nreou-RroA-RCAopCaotphaieths)ie, se)s, pesepcieaclilayllfyofcoucsuinsigngononththeerreelleevvaannccee of tthhee ffuunnccttioionnaall ddiissrruuppttiioonn ooff these Rhhoo GGTTPPaasseessaannddththeeirirrergeguulaltaotroyryprportoetienisnisninenueruornoanl aclelcles.llTs.heTuhneudnedrsetrasntadnidnigngofotfhteheppatahthoopphhyysisoiolologgiciacal llilninkkssuunnddeerrllyyiinngg tthheessee conditions iiss ooffppaarrtticicuulalarr iinntteerreessttccoonnssiiddeerriinnggtthheeggrroowwiinngginintteerreessttoonnththeebbioiolologgicicaallssigignnifiifcicaanncceeooffaabbnnoorrmmaallRRaacc ssiiggnnaalliinnggiinnhhuummaannddisiseeaasseeaannddtthheerreeppoorrttooffaadddditiitoionnaal lccoohhoorrtstsoof faaffefeccteteddininddivivididuuaalsl.s
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