MeCP2 and Rett syndrome: reversibility and potential avenues for therapy

Abstract

Mutations in the X-linked gene MECP2 (methyl CpG-binding protein 2) are the primary cause of the neurodevelopmental disorder RTT (Rett syndrome), and are also implicated in other neurological conditions. The expression product of this gene, MeCP2, is a widely expressed nuclear protein, especially abundant in mature neurons of the CNS (central nervous system). The major recognized consequences of MECP2 mutation occur in the CNS, but there is growing awareness of peripheral effects contributing to the full RTT phenotype. MeCP2 is classically considered to act as a DNA methylation-dependent transcriptional repressor, but may have additional roles in regulating gene expression and chromatin structure. Knocking out Mecp2 function in mice recapitulates many of the overt neurological features seen in RTT patients, and the characteristic postnatally delayed onset of symptoms is accompanied by aberrant neuronal morphology and deficits in synaptic physiology. Evidence that reactivation of endogenous Mecp2 in mutant mice, even at adult stages, can reverse aspects of RTT-like pathology and result in apparently functionally mature neurons has provided renewed hope for patients, but has also provoked discussion about traditional boundaries between neurodevelopmental disorders and those involving dysfunction at later stages. In the present paper we review the neurobiology of MeCP2 and consider the various genetic (including gene therapy), pharmacological and environmental interventions that have been, and could be, developed to attempt phenotypic rescue in RTT. Such approaches are already providing valuable insights into the potential tractability of RTT and related conditions, and are useful pointers for the development of future therapeutic strategies.

Clinical and biological progress over 50 years in Rett syndrome

“…[185][186][187][188] These include efforts to target the various brain systems and downstream cellular processes affected in RTT as well as approaches that target the root cause of the disorderMeCP2 dysfunction (see Fig. 4).…”

Rett Syndrome: Reaching for Clinical Trials

“…Therapeutic targets for RTT are either aimed at reversing the loss-of-function mutation in MECP2 or modifying its downstream pathways, including neurotransmitter receptor systems, neurotrophins, and their intracellular signaling pathways (Tables 1 and 2) [63][64][65]. We follow the standard convention: Bpreclinical^is used for experiments done in experimental animal models, and Bclinical^for tests performed in humans.…”

Genetic approach to the patient and the family: A Rett Syndrome case with R270X mutation in MECP2 gene

“…Rett Syndrome (RTT) (MIM#312750) is a severe neurodevelopmental disorder that primarily affects girls [1]. The incidence of disease is approximately 1 in 10,000 female births [1].…”

“…The incidence of disease is approximately 1 in 10,000 female births [1]. First time, the diagnostic criteria for RTT in female patients have been described in 2002 [2].…”