MECP2 and the biology of MECP2 duplication syndrome

Abstract

MECP2 duplication syndrome (MDS), a rare X‐linked genomic disorder affecting predominantly males, is caused by duplication of the chromosomal region containing the methyl CpG binding protein‐2 (MECP2) gene, which encodes methyl‐CpG‐binding protein 2 (MECP2), a multi‐functional protein required for proper brain development and maintenance of brain function during adulthood. Disease symptoms include severe motor and cognitive impairment, delayed or absent speech development, autistic features, seizures, ataxia, recurrent respiratory infections, and shortened lifespan. The cellular and molecular mechanisms by which a relatively modest increase in MECP2 protein causes such severe disease symptoms are poorly understood and consequently there are no treatments available for this fatal disorder. This review summarizes what is known to date about the structure and zcomplex regulation of MECP2 and its many functions in the developing and adult brain. Additionally, recent experimental findings on the cellular and molecular underpinnings of MDS based on cell culture and mouse models of the disorder are reviewed. The emerging picture from these studies is that MDS is a neurodegenerative disorder in which neurons die in specific parts of the central nervous system, including the cortex, hippocampus, cerebellum, and spinal cord. Neuronal death likely results from astrocytic dysfunction, including a breakdown of glutamate homeostatic mechanisms. The role of elevations in the expression of glial acidic fibrillary protein (GFAP) in astrocytes and the microtubule‐associated protein, Tau, in neurons to the pathogenesis of MDS is discussed. Lastly, potential therapeutic strategies to potentially treat MDS are discussed.

Auditory Dysfunction in Animal Models of Autism Spectrum Disorder

“…The MECP2 gene encodes methyl-CpG binding protein (MeCP2) that acts as a regulator of gene expression, playing an important role in prenatal neurogenesis and postnatal synaptic development, function, and plasticity ( Brand et al, 2021 ). MECP2 genetic loss of function is associated with intellectual disability and Rett syndrome ( Brand et al, 2021 ), whereas its duplication is characterized by motor and cognitive impairments, delayed or absent speech, seizures, and ataxia ( D’Mello, 2021 ). In both situations, ASD-related phenotypes are often times present.…”

The Role of Recombinant AAV in Precise Genome Editing

“…An example of this is Rett syndrome, caused by mutations in the MECP2 gene ( Amir et al, 1999 ). MECP2 expression is highly regulated in vivo , and either too much or too little expression leads to toxicity ( Montgomery et al, 2018 ; D'Mello, 2021 ). Most gene therapy vectors utilize heterologous promoters since the natural chromosomal promoters of most disease-associated genes exceed the coding capacity of AAV vectors.…”

Early life stress exacerbates behavioural and neuronal alterations in adolescent male mice lacking methyl-CpG binding protein 2 (Mecp2)

“…An increasing amount of evidence suggest that Mecp2 has a role on the susceptibility to early life environmental disturbances and thus on determining the coping strategies that animals develop later in life ( Abellán-Álvaro et al, 2021 ; Sánchez-Lafuente et al, 2022 ). Dosage-variation on functional MECP2 during human neurodevelopment have been described in RTT, predominantly affecting females ( Amir et al, 1999 ), but also affecting males in MDS ( D’Mello, 2021 ; Pascual-Alonso et al, 2021 ) and in cases of somatic mosaicism and intellectual disability associated with RTT ( Orrico et al, 2000 ; Kudo et al, 2002 ; Topçu et al, 2002 ; Venâncio et al, 2007 ). In the case of patients, these early life environmental disturbances are even more complicated to assess due to additional motor disabilities and communication impairments among other phenotypical manifestations.…”

“…Nonetheless, MECP2 mutations have also been identified in male patients with intellectual disabilities ( Orrico et al, 2000 ; Kudo et al, 2002 ), as well as cases of somatic mosaicism associated with RTT ( Topçu et al, 2002 ; Venâncio et al, 2007 ). Additionally, MECP2 duplication syndrome (MDS), which only manifests in males, is characterised by intellectual disability, heightened anxiety-like behaviours, seizures, and recurrent respiratory infections among others ( D’Mello, 2021 ; Pascual-Alonso et al, 2021 ). The plethora of MECP2 -related disorders demonstrates that this gene occupies a central role in the post-natal development of the brain in both sexes.…”