Mutations in methyl-CpG-binding protein 2 (MECP2) in males can lead to various phenotypes, ranging from neonatal encephalopathy to intellectual disability.
In 2009, four families with a distal duplication of Xq28 not including MECP2 and mediated by low-copy repeats (LCRs) designated "K" and "L" were reported with intellectual disability and epilepsy.
The nervous system is so acutely sensitive to the dose of methyl-CpG-binding protein 2 (MeCP2) that even a twofold change in MeCP2 protein-either increased or decreased-results in distinct disorders with overlapping features including ID, autistic behavior, and severe motor dysfunction.
Specific mutations in MECP2 cause Rett syndrome (RTT) in females whereas other mutations in the same gene cause several other syndromes in males, including X-linked intellectual disability (with and without spasticity) (OMIM 300055) and X-linked intellectual disability due to increased dosage of MECP2 (OMIM 300260).
We report here the first missense variant located in AT-hook domain 1 and we underline the importance of MECP2 substitutions outside the canonical MeCP2 domains in X-linked intellectual disability.
Here we report on the identification of the p.Ala140Val mutation in the MECP2 gene in 4 males and 3 females of a large Caucasian family affected with X-linked intellectual disability.
Normal levels of the methyl CpG-binding protein 2 (MeCP2) are critical to neurologic functioning, and slight alterations result in intellectual disability and autistic features.
Maintenance of an appropriate level of MeCP2 appears integral to the function of healthy neurons as patients with increased levels of MeCP2, owing to duplication of the Xq28 region encompassing the MECP2 locus, also present with intellectual disability and progressive neurologic symptoms.
Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing.
Overall, 16p11.2 CNV was associated with altered expression of genes and networks that converge on multiple hypotheses of ASD pathogenesis, including synaptic function (e.g., NRXN1, NRXN3), chromatin modification (e.g., CHD8, EHMT1, MECP2), transcriptional regulation (e.g., TCF4, SATB2), and intellectual disability (e.g., FMR1, CEP290).
Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2, CHD8 and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders.
We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C.
This finding emphasizes the need to consider MECP2 sequencing in females with non-classic Rett phenotypes, particularly those with intellectual disability and neuropsychiatric features.
The purpose of this study was to investigate the role of evolutionarily conserved cis-elements in regulating the post-transcriptional expression of the MECP2 gene and to explore their possible correlations with a mutation that is known to cause mental retardation.
In conclusion, i) MECP2 is one of the most important genes in the diagnosis of genetic intellectual disability in females; ii) MECP2 must be studied not only in patients with classical/atypical Rett syndrome but also in patients with other phenotypes related to Rett syndrome; and iii) for the new variants, it is important to perform complementary studies, including the analysis of large populations of healthy individuals and the use of in silico programs.
Mecp2 is a transcriptional repressor protein that is mutated in Rett syndrome, a neurodevelopmental disorder that is the second most common cause of mental retardation in women.