Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression

Abstract

The etiology of mental retardation remains elusive in the majority of cases. Microdeletions within chromosomal bands 5q14.3q15 were recently identified as a recurrent cause of severe mental retardation, epilepsy, muscular hypotonia, and variable minor anomalies. By molecular karyotyping we identified two novel 2.4- and 1.5-Mb microdeletions of this region in patients with a similar phenotype. Both deletions contained the MEF2C gene, which is located proximally to the previously defined smallest region of overlap. Nevertheless, due to its known role in neurogenesis, we considered MEF2C as a phenocritical candidate gene for the 5q14.3q15 microdeletion phenotype. We therefore performed mutational analysis in 362 patients with severe mental retardation and found two truncating and two missense de novo mutations in MEF2C, establishing defects in this transcription factor as a novel relatively frequent autosomal dominant cause of severe mental retardation accounting for as much as 1.1% of patients. In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. We therefore conclude that the phenotypic overlap of patients with MEF2C mutations and atypical Rett syndrome is due to the involvement of a common pathway.

SpDamID: Marking DNA Bound by Protein Complexes Identifies Notch-Dimer Responsive Enhancers

“…Although we did not see evidence of methylation at nearby regions in the Hes1 (−8kb) and Nrarp (−6kb) promoters, we identified reproducible enrichment of DpnI digested fragments at −8kb, −10kb and −12kb relative to the transcription start site (TSS) within the Nrarp regulatory region. We also detected consistent methylation by Notch SpDamID near the TSS of the Notch target Cdh6 ( Figure 1E, (Bielesz et al, 2010)) and Mef2c SpDamID labeled near the Mef2c target, Cdkl5 (Zweier et al, 2010). These results demonstrate that SpDamID can identify TF specific complexes on genomic sites in spite of utilization of shared co-activators.…”

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

“…Among them, Mef2c (myocyte enhancer factor 2C) showed a trend toward downregulation that did not reach the defined Fold Change threshold; it was, however, included in the validation set as it has been found mutated in patients with a RTT-like phenotype. 24,25 Among these 92 genes, a set of 11 genes was selected based on their biological function for further validation by qRT-PCR (Table 1) …”

Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals

“…Histone deacetylases (HDACs) are involved in neuronal dendritic growth regulation and regulate transcription factors activity associated to ASD or intellectual disability, such as MECP2 49 or MEF2C. 50,51 One may speculate that the alternative transcribed protein, missing the nuclear export signal, may have a dominant negative effect. However, we failed to demonstrate any altered splicing in mRNA extracted from the patient lymphoblastoid cells.…”