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MeCP2 is a protein that functions as a key factor in epigenetic transcriptional regulation. Mutations in MECP2 gene have been reported as being the major cause of Rett syndrome. These mutations may also cause a wide spectrum of neurological disorders in males. Here, we report the identification of the mutation p.P405L in a 19-year-old Brazilian male with mental retardation. This variant is localized in a highly conserved aminoacid from the carboxy terminal domain and may affect the protein function. Segregation analysis on the patient's mother revealed that this is a de novo mutation and it was not identified in the control sample. The programs SIFT, PolyPhen and A-GVGD considered that the p.P405L may be damaging. Despite the high frequency of non pathogenic variants that have been identified in this gene, our data lead us to consider the p.P405L a disease-causing mutation.

MeCP2 is a protein that selectively binds to methylated cytosines through its methyl-CpG-binding domain (MBD) and connects DNA methylation to transcriptional repression. Mutations in MECP2 gene, located in Xq28, have been reported as being the major cause of Rett syndrome and are also associated with some cases of X-linked mental retardation in both males and females. In this study, we present the first screening in the MECP2 gene in a Brazilian cohort of 239 unrelated males with idiopathic mental retardation. Eight sequence variations were observed in 10 patients: one novel putative pathogenic variant, two never described variants of unknown pathogenic value and five non-pathogenic variations. We conclude that in mentally retarded Brazilian males, non-pathogenic variants in the MECP2 gene are more common than actual pathogenic mutations, and therefore alterations in this gene have a weak relationship with mental retardation in males.

In mammals, methyl-CpG binding proteins play a significant role in the control of gene expression through their association with chromatin-remodeling complexes. Mutations in the gene coding for methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome and have also been reported in a number of X-linked mental retardation diseases. In this study, DNA samples from 363 male individuals with syndromic and non-syndromic mental retardation and other psychiatric diseases were screened for A140V (419C>T) mutation in the MECP2 gene, considered the most frequent MECP2 mutation in males. No 419C>T was found suggesting that the A140V mutation in the MECP2 gene is not a common cause of mental retardation in males. Recently, a new and abundant isoform of MECP2 was described, which has an alternative N-terminus, translated from exon 1, that was previously thought to be non-coding and has been excluded from many mutational screening, as well, the 5' and 3' UTR regions. We consider essential proceeding further screening in the whole extension of the MECP2 gene using clinically well-documented and larger sized sample to assure the overall contribution of MECP2 to mental retardation.