Abstract
Methyl CpG binding protein 2 (MECP2) is located at Xq28 and is a multifunctional gene with ubiquitous expression. Loss-of-function mutations in MECP2 are associated with Rett syndrome (RTT), which is a well-characterized disorder that affects mainly females. In boys, however, mutations in MECP2 can generate a wide spectrum of clinical presentations that range from mild intellectual impairment to severe neonatal encephalopathy and premature death. Thus, males can be more difficult to classify and diagnose than classical RTT females. In addition, there are some variants of unknown significance in MECP2, which further complicate the diagnosis of these children. Conversely, the entire duplication of the MECP2 gene is related to MECP2 duplication syndrome (MDS). Unlike in RTT, in MDS, males are predominantly affected. Usually, the duplication is inherited from an apparently asymptomatic carrier mother. Both syndromes share some characteristics, but also differ in some aspects regarding the clinical picture and evolution. In the following review, we present a thorough description of the different types of MECP2 variants and alterations that can be found in males, and explore several genotype–phenotype correlations, although there is still a lot to understand.
Highlights
Fundació Per la Recerca Sant Joan de Déu, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain; Institut de Recerca Sant Joan de Déu, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain; Clinical Genetics, Molecular and Genetic Medicine Section, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Methyl CpG binding protein 2 (MECP2) is a dosage-sensitive gene because loss-of-function mutations lead to Rett syndrome (RTT), but whole gene duplication leads to MECP2 duplication syndrome (MDS)
Classification of these male patients into the mentioned groups should help clinicians and geneticists to better understand the phenotypes that arise from alterations in MECP2 and to establish the molecular basis for the genotype–phenotype correlation
Summary
Methyl CpG binding protein 2 (MECP2) (OMIM *300005) encodes the protein MeCP2 and is located in the Xq28 region which can be inactivated for gene dosage compensation of the X chromosome in females [1]. MECP2_e1 is the most abundant isoform in the brain the ratio between the two isoforms varies across different tissues; for example, MECP2_e2 is more abundant in fibroblasts [2]. Even though both isoforms share the majority of their sequence and the main functional domains, they are not completely redundant. MECP2 is a dosage-sensitive gene because loss-of-function mutations lead to RTT, but whole gene duplication leads to MDS. This must be taken into consideration when looking for a treatment. We would like to take a deeper look into the male cases harboring mutations and alterations in MECP2 since much remains to be understood
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