Abstract

Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) are neurodevelopmental disorders caused by alterations in the methyl-CpG binding protein 2 (MECP2) gene expression. A relationship between MECP2 loss-of-function mutations and oxidative stress has been previously documented in RTT patients and murine models. To date, no data on oxidative stress have been reported for the MECP2 gain-of-function mutations in patients with MDS. In the present work, the pro-oxidant status and oxidative fatty acid damage in MDS was investigated (subjects n = 6) and compared to RTT (subjects n = 24) and healthy condition (subjects n = 12). Patients with MECP2 gain-of-function mutations showed increased oxidative stress marker levels (plasma non-protein bound iron, intraerythrocyte non-protein bound iron, F2-isoprostanes, and F4-neuroprostanes), as compared to healthy controls (P ≤ 0.05). Such increases were similar to those observed in RTT patients except for higher plasma F2-isoprostanes levels (P < 0.0196). Moreover, plasma levels of F2-isoprostanes were significantly correlated (P = 0.0098) with the size of the amplified region. The present work shows unique data in patients affected by MDS. For the first time MECP2 gain-of-function mutations are indicated to be linked to an oxidative damage and related clinical symptoms overlapping with those of MECP2 loss-of-function mutations. A finely tuned balance of MECP2 expression appears to be critical to oxidative stress homeostasis, thus shedding light on the relevance of the redox balance in the central nervous system integrity.

Highlights

  • Methylated-CpG binding protein 2 (MeCP2) is a nuclear protein encoded by the X-linked methyl-CpG binding protein 2 (MECP2) gene (OMIMÃ300005)

  • Loss-of-function mutations in MECP2 is the main cause of Rett syndrome (RTT), which is a neurodevelopmental disease with severe cognitive impairment occurring at a ratio of approximately 1:10,000 girls [3,4]

  • Gain-of-function mutations in relation to MECP2 lead to a severe neurodevelopmental disorder, named MECP2 duplication syndrome (MDS) or MECP2 triplication syndrome [6,7,8]

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Summary

Introduction

Methylated-CpG binding protein 2 (MeCP2) is a nuclear protein encoded by the X-linked MECP2 gene (OMIMÃ300005). Loss-of-function mutations in MECP2 is the main cause of Rett syndrome (RTT), which is a neurodevelopmental disease with severe cognitive impairment occurring at a ratio of approximately 1:10,000 girls [3,4]. RTT is not the only known pathological condition related to MECP2 mutations, as a wide series of conditions, collectively termed as MECP2-related disorders [5], has been reported. These disorders include asymptomatic female carriers, boys with MECP2 mutations typically causing a RTT phenotype in girls, and rare individuals with mutations in MECP2 showing other neurodevelopmental disorders [5]. The phenotypes include major cognitive and motor deficits, stunted motor development, early onset hypotonia, epilepsy, and progressive spasticity, clinical features which are overlapping with some of those seen in RTT [6,7]

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