Microcephaly-dystonia due to mutated PLEKHG2 with impaired actin polymerization
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.
KeywordsMicrocephaly Dystonia PLEKHG2 Actin
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.
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
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