Unraveling Molecular Pathways Altered in MeCP2-Related Syndromes, in the Search for New Potential Avenues for Therapy.

Alba-Aina Castells,Àngels Garcia-Cazorla,Alba Tristán-Noguero,Elisenda Cortès-Saladelafont,Judith Armstrong,Soledad Alcántara,Rafel Balada,Ainhoa Pascual-Alonso,Mar O’Callaghan

doi:10.3390/biomedicines9020148

Abstract

Methyl-CpG-binding protein 2 (MeCP2) is an X-linked epigenetic modulator whose dosage is critical for neural development and function. Loss-of-function mutations in MECP2 cause Rett Syndrome (RTT, OMIM #312750) while duplications in the Xq28 locus containing MECP2 and Interleukin-1 receptor-associated kinase 1 (IRAK1) cause MECP2 duplication syndrome (MDS, OMIM #300260). Both are rare neurodevelopmental disorders that share clinical symptoms, including intellectual disability, loss of speech, hand stereotypies, vasomotor deficits and seizures. The main objective of this exploratory study is to identify novel signaling pathways and potential quantitative biomarkers that could aid early diagnosis and/or the monitoring of disease progression in clinical trials. We analyzed by RT-PCR gene expression in whole blood and microRNA (miRNA) expression in plasma, in a cohort of 20 females with Rett syndrome, 2 males with MECP2 duplication syndrome and 28 healthy controls, and correlated RNA expression with disease and clinical parameters. We have identified a set of potential biomarker panels for RTT diagnostic and disease stratification of patients with microcephaly and vasomotor deficits. Our study sets the basis for larger studies leading to the identification of specific miRNA signatures for early RTT detection, stratification, disease progression and segregation from other neurodevelopmental disorders. Nevertheless, these data will require verification and validation in further studies with larger sample size including a whole range of ages.

Highlights

Rett Syndrome (RTT) patients diagnosed as typical RTT with known mutations in the methyl-CpG-binding protein 2 (MECP2) gene entered the study, ranging from 5 to 33 years old at the time of blood extraction
Two young male MDS patients, to serve as reference of increased Methyl-CpG-binding protein 2 (MeCP2) function, and one asymptomatic female carrier of MECP2 duplication were included in the study
We found a positive correlation with age for MECP2 E2 in control samples but not within

Summary

Introduction

Methyl-CpG-binding protein 2 (MeCP2) is a calcium-dependent DNA-binding protein involved in chromatin organization [1,2], transcriptional regulation [3,4] and control of protein translation via microRNA (miRNA)-mediated mechanisms [5]. X-linked and its dosage is critical for neural development and function, as both defect and excess of MeCP2 function have severe neurological consequences. Rett syndrome (RTT, OMIM #312750) is mainly caused by loss-of-function mutations in MECP2, and MECP2 duplication syndrome (MDS, OMIM #300260) is associated with duplications in the Xq28 locus, with a minimal region of duplication containing MECP2 and the adjacent gene. Interleukin-1 receptor-associated kinase 1 (IRAK1) [6].

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