In particular, beta-actin is a critical player in several cellular functions, ranging from cell motility and the maintenance of cell shape and polarity to transcription regulation. Interestingly, several syndromes associated with mental retardation are characterized by cortical dendritic abnormalities, and the neuronal cytoskeleton is essential for dendritic developmental processes. It includes microfilaments, neurofilaments and microtubules, each one being formed by a major protein, i.e., actin, neurofilament and tubulin, respectively. Re syndrome, the second commonest cause of severe mental retardation in the female gender, is represented by a devastating neurodevelopmental disorder with a wide phenotypical heterogeneity which is caused in the overwhelming majority of cases by loss-of-function de novo sporadic mutations in the X-linked gene encoding the methyl-CpG binding protein 2. In its classical phenotype, R is characterized by an apparently normal development in the first few months followed by loss of neurodevelopmental milestones in a 4-stage progression. Increasing evidence supports the concept that R is associated with impairment of dendritic arborization. Several studies have described neuronal abnormalities in R human brains, and in male Mecp2-mutant mice. Overall, this body of research suggests that MECP2 deficiency mutations are involved in cellular mechanisms regulating short term dynamics of dendritic spines early in development within the frame of maximum neural plasticity. However, the underlying cause for the dendritic arborization impairment in R is still largely unknown. While prior studies on Mecp2-deficient brains show striking changes in neuronal maturation, recent evidence indicates that MeCP2 deficiency affects microtubule dynamics in R astrocytes and impairs microtubule stability in R primary fibroblast cultures. These data suggest that MeCP2 has a stabilizing role on microtubule dynamics and that its deficiency could lead to impaired microtubule stability which may at least partly underlie the dendritic abnormalities Isoacteoside detected in R brains. We have previously demonstrated the existence of an abnormal erythrocyte shape in typical R patients showing a striking prevalence of circulating leptocytes with enhanced membrane oxidative stress. Therefore, in the present study, we tested the hypothesis that a beta-actin deficiency with an increased oxidative pos ranslational modification could underlie the red blood cells shape abnormalities in patients affected by the typical form of the disease. The data of the present study demonstrate, for the first time, the occurrence of a beta-actin deficiency and its oxidative PTMs in the inner interface of the erythrocytes membrane from patients affected by R . The combination of these adverse factors can lead to an altered erythrocyte Gomisin-D cytoskeletal network organization. Therefore, it is likely that a cytoskeletal disorganization is ubiquitously present in the cells of R patients. It is well known that beta-actin is an essential protein in the RBCs cytoskeleton which represents a major structural component for the horizontal tensile forces in the inner membrane. The resulting imbalance between horizontal and vertical tensile forces could lead to the abnormal RBCs shape detectable in R .