Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Mar 31;9(4):835.
doi: 10.3390/cells9040835.

Rho GTPase Regulators and Effectors in Autism Spectrum Disorders: Animal Models and Insights for Therapeutics

Daji Guo  1 , Xiaoman Yang  1 , Lei Shi  1
Affiliations
Review

Rho GTPase Regulators and Effectors in Autism Spectrum Disorders: Animal Models and Insights for Therapeutics

Daji Guo et al. Cells. .

Abstract

The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. Recent evidence suggests that dysfunction of Rho GTPase signaling contributes substantially to the pathogenesis of autism spectrum disorder (ASD). It has been found that 20 genes encoding Rho GTPase regulators and effectors are listed as ASD risk genes by Simons foundation autism research initiative (SFARI). This review summarizes the clinical evidence, protein structure, and protein expression pattern of these 20 genes. Moreover, ASD-related behavioral phenotypes in animal models of these genes are reviewed, and the therapeutic approaches that show successful treatment effects in these animal models are discussed.

Keywords: GTPase-activating protein; Rho GTPase; animal model; autism spectrum disorder; behavior; guanine nuclear exchange factor.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overlap of human gene sets of RhoGEFs, RhoGAPs, and Rho effectors with autism spectrum disorder (ASD) risk genes in Simons foundation autism research initiative (SFARI).
Figure 2
Figure 2
Schematics of protein domain structures of 20 ASD-related RhoGEFs, RhoGAPs, and Rho effectors. (A) Seven ASD-related RhoGEF protein domain architectures. Arhgef9 (which has two variants, CB I and CB II), Trio, P-Rex1, and Arhgef10 belong to Dbl family, which is characterized by a DH domain (dark violet) and a PH domain (light pink). Dock8, Dock1, and Dock4 belong to Dock family, which contains two main domains, DHR1 domain (dark orchid) and DHR2 domain (dark magenta). (B) Seven ASD-related RhoGAP protein domain architectures. In addition to a common catalytic GAP domain (purple), most RhoGAPs have multiple other functional domains. (C) Six ASD-related Rho effector protein domain architectures. All protein structures are generated using DOG 2.0 (Domain Graph, version 2.0) [94] based on corresponding mouse protein sequences except ARHGAP11B, for which human protein structure is shown as no homologs exist in rodents. Scales represent amino acid numbers of 500. AID, Autoinhibitory Domain; ASH, ASPM/SPD2/Hydin; BAR, Bin/Amphiphysin/Rvs; C1, binding site of diacylglycerol (DAG); C2, binding site of Ca2+; CBR, β-catenin-binding region; CC, coiled-coil; CRAL-TRIO, cellular retinaldehyde-binding protein and TRIO guanine exchange factor; CTR, C-terminal region with proline-rich; DEP, Disheveled, EGL-10, Pleckstrin; DH, Dbl Homology; DHR1, Dock homology region 1; DHR2, Dock homology region 2; F-BAR, Fes-Cip4 homology Bin/Amphiphysin/Rvs; FF, domain with two conserved phenylalanine residues; GAP, GTPase-activating proteins; GBD, guanosine triphosphate (GTP)-binding; GBR, GABARAP-binding region; Ig, immunoglobulin; IP4P, inositol polyphosphate 4-phosphatase; IQ, short calmodulin-binding motif containing conserved isoleucine and glutamine residues; PBD, p21-binding domain; PDZ, PSD95/SAP90, DlgA, ZO-1; pG1, pseudoGTPase domain 1; pG2, pseudoGTPase domain 2; PH, Pleckstrin-Homology; PIX, Pak-interacting exchange factor; Pro, proline-rich; PX, phox homology; Scar, Scar homology; SH3, Src homology 3; WH, WASF homology.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Elsabbagh M., Divan G., Koh Y.-J., Kim Y.S., Kauchali S., Marcin C., Montiel-Nava C., Patel V., Paula C.S., Wang C., et al. Global Prevalence of Autism and Other Pervasive Developmental Disorders. Autism Res. 2012;5:160–179. doi: 10.1002/aur.239. - DOI - PMC - PubMed
    1. Baron-Cohen S., Gullon-Scott F., Allison C., Williams J., Bolton P., E Matthews F., Brayne C. Prevalence of autism-spectrum conditions: UK school-based population study. Br. J. Psychiatry. 2009;194:500–509. doi: 10.1192/bjp.bp.108.059345. - DOI - PubMed
    1. Kim Y.S., Leventhal B.L., Koh Y.-J., Fombonne E., Laska E., Lim E.-C., Cheon K.-A., Kim S.-J., Kim Y.-K., Lee H., et al. Prevalence of Autism Spectrum Disorders in a Total Population Sample. Am. J. Psychiatry. 2011;168:904–912. doi: 10.1176/appi.ajp.2011.10101532. - DOI - PubMed
    1. Kočovská E., Biskupstø R., Gillberg I.C., Ellefsen A., Kampmann H., Stóra T., Billstedt E., Gillberg C. The Rising Prevalence of Autism: A Prospective Longitudinal Study in the Faroe Islands. J. Autism Dev. Disord. 2012;42:1959–1966. doi: 10.1007/s10803-012-1444-9. - DOI - PubMed
    1. Sun X., Allison C., E Matthews F., Sharp S., Auyeung B., Baron-Cohen S., Brayne C. Prevalence of autism in mainland China, Hong Kong and Taiwan: a systematic review and meta-analysis. Mol. Autism. 2013;4:7. doi: 10.1186/2040-2392-4-7. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances