Abstract
Rearrangement of the actin cytoskeleton is controlled by RhoGTPases which are activated by RhoGEFs. We identified homozygosity for Arg204Trp mutation in the Rho guanidine exchange factor (RhoGEF) PLEKHG2 gene in five patients with profound mental retardation, dystonia, postnatal microcephaly, and distinct neuroimaging pattern. The activity of the mutant PLEKHG2 was significantly decreased, both in basal state and when Gβγ- or lysophosphatidic acid (LPA)-stimulated. SDF1a-stimulated actin polymerization was significantly impaired in patient cells, and this abnormality was duplicated in control cells when PLEKHG2 expression was downregulated. These results underscore the role of PLEKHG2 in actin polymerization and delineate the clinical and radiological findings in PLEKHG2 deficiency.
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Acknowledgments
The clinical and molecular parts were performed within the frame of the Germany, Israel, and Palestine Trilateral research grant 443 ISR-113/228/0-1 of the Deutsche Forschungsgemeinschaft on Inborn Leukoencephalopathies.
Authors’ contribution
SE, HW, SC, and OE conceived and designed the experiments. HW, BY, and YC performed the experiments. HW, BY, SC, and OE analyzed the data. SE, JG, SC, and OE wrote the paper, SE, TD, JG, and OA undertook patient management, collection of samples, and delineation of the phenotype.
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Simon Edvardson and Talya Dor share equal contribution
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Supplemental Figure 1
the structure of the PLEKHG2 DH-PH domains. Based on the crystal coordinates of trio DH-PH domain [13], the molecular structure of the PLEKHG2 DH-PH domains was constructed using the UCSF chimera package [16]. A-B, the location of R204 is shown in the space-filling (A) and ribbon (B) models of the PLEKHG2 DH-PH domains. C, the ribbon model of the trio DH-PH domains in complex with Rac. The location of trio L1398 equivalent to PLEKHG2 R204 is indicated. (GIF 228 kb)
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Edvardson, S., Wang, H., Dor, T. et al. Microcephaly-dystonia due to mutated PLEKHG2 with impaired actin polymerization. Neurogenetics 17, 25–30 (2016). https://doi.org/10.1007/s10048-015-0464-y
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DOI: https://doi.org/10.1007/s10048-015-0464-y