MECP2 Duplication Syndrome: Evidence of Enhanced Oxidative Stress. A Comparison with Rett Syndrome - PubMed (original) (raw)

Comparative Study

. 2016 Mar 1;11(3):e0150101.

doi: 10.1371/journal.pone.0150101. eCollection 2016.

Claudio De Felice 2, Silvia Leoncini 1 3, Rikke S Møller 4 5, Gloria Zollo 1 3, Sabrina Buoni 3, Alessio Cortelazzo 3, Roberto Guerranti 6, Thierry Durand 7, Lucia Ciccoli 1, Maurizio D'Esposito [ 8](#full-view-affiliation-8 "Institute of Genetics and Biophysics "A. Buzzati-Traverso", Naples, Italy.") 9, Kirstine Ravn 10, Joussef Hayek 3

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Comparative Study

MECP2 Duplication Syndrome: Evidence of Enhanced Oxidative Stress. A Comparison with Rett Syndrome

Cinzia Signorini et al. PLoS One. 2016.

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1

Fig 1. Graphical view of the MECP2 duplications/triplication.

Graphical view of the MECP2 duplications/triplication was created with custom tracks in the UCSC genome browser (GRCh37/hg19), (Patient 1 was identified with a triplication). The involved regions are shown in blue and MECP2 is marked by a red circle.

Fig 2

Fig 2. Oxidative stress marker plasma levels in MDS and RTT.

Levels of NPBI, plasma free F2-IsoPs, F4-NeuroPs, and F2-dihomo-IsoPs in MDS are compared with those of RTT and healthy control subjects. All the statistical significant differences were reported. Legend: ANOVA, analysis of variance; F2-dihomo-isoPs, F2-dihomo-isoprostanes; F2-IsoPs, F2-isoprostanes; F4-NeuroPs, F4-neuroprostanes; IE-NPBI, intraerythrocyte non protein bound iron; MDS, MECP2 Duplication Syndrome; p-NPBI, plasma non protein bound; RTT, Rett syndrome.

Fig 3

Fig 3. Relationship between plasma F2-IsoPs and Xq28 size (univariate regression analysis).

A positive linear relationship of plasma F2-IsoPs vs. Xq28 duplication/triplication size is showed. The strength of the relationship is indicated by the correlation coefficient (r = 0.9181, P = 0.0098). The linear regression equation was reported.

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Grants and funding

The present work was funded by the Tuscan Region (Bando Salute 2009; “Antioxidants—omega-3 polyunsaturated Fatty Acids, lipoic acid—supplementation in Rett syndrome: A novel approach to therapy,” RT no. 142). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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