MECP2 coding sequence and 3′UTR variation in 172 unrelated autistic patients

Abstract

Mutations in the coding sequence of the methyl‐CpG‐binding protein 2 gene (MECP2), which cause Rett syndrome (RTT), have been found in male and female autistic subjects without, however, a causal relation having unequivocally been established. In this study, the MECP2 gene was scanned in a Portuguese autistic population, hypothesizing that the phenotypic spectrum of mutations extends beyond the traditional diagnosis of RTT and X‐linked mental retardation, leading to a non‐lethal phenotype in male autistic patients. The coding region, exon–intron boundaries, and the whole 3′UTR were scanned in 172 patients and 143 controls, by Detection of Virtually All Mutations‐SSCP (DOVAM‐S). Exon 1 was sequenced in 103 patients. We report 15 novel variants, not found in controls: one missense, two intronic, and 12 in the 3′UTR (seven in conserved nucleotides). The novel missense change, c.617G > C (p.G206A), was present in one autistic male with severe mental retardation and absence of language, and segregates in his maternal family. This change is located in a highly conserved residue within a region involved in an alternative transcriptional repression pathway, and likely alters the secondary structure of the MeCP2 protein. It is therefore plausible that it leads to a functional modification of MeCP2. MECP2 mRNA levels measured in four patients with 3′UTR conserved changes were below the control range, suggesting an alteration in the stability of the transcripts. Our results suggest that MECP2 can play a role in autism etiology, although very rarely, supporting the notion that MECP2 mutations underlie several neurodevelopmental disorders. © 2007 Wiley‐Liss, Inc.

A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations

“…More recent studies have identified mutations in MECP2 regulatory regions in autistic boys (13,34), rather than protein coding mutations found in female Rett syndrome patients. These results may be explained on the basis of the extra (inactive) copy of the X chromosome providing redundancy or buffering to severe protein-coding mutations in females.…”

Rett Syndrome and MeCP2

“…Studies in control and autistic patients suggest that there are numerous variations in 3′UTR between them, and these transcripts have different translational efficiencies. Some of these transcript variants are more unstable and undergo transcriptional degradation (Coutinho et al 2007). Newnham et al, reported the presence of cis-acting elements which can regulate the polyadenylation of human MECP2 gene and mutations of which can reduce the polyadenylation efficiency.…”

“…Reduced MECP2 expression in autistic patients has been associated with increased MECP2 promoter DNA methylation (Nagarajan et al 2006(Nagarajan et al , 2008. Moreover, MECP2 mutations within the coding regions (Carney et al 2003;Beyer et al 2002;Lam et al 2000;Loat et al 2008) and sequence variants within the MECP2 3′UTR (Shibayama et al 2004;Coutinho et al 2007) are also found in autistic patients, indicating the potential involvement of these sequence variations in altered expression of MECP2 in autism. Not only reduced MECP2 expression, but also overexpression of MECP2 is found in ASD patients (Kuwano et al 2011).…”

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

“…Their relative rarity may be in part because not all regulatory elements occur immediately 5 0 to the genes that they regulate. Indeed, many such elements are located within the first exon, within introns [Cecchini et al, 2009] or within 5 0 or 3 0 untranslated regions (UTRs); regulatory elements within intronic sequences and UTRs are less likely to be screened for mutations [Chatterjee and Pal, 2009;Chen et al, 2006a,b], particularly if the UTRs are large (e.g., MECP2; MIM] 300005) [Coutinho et al, 2007]. Recently, a whole new category of pathological mutation has been recognized within the 3 0 UTRs of human genes: genetic variants located in microRNA target sites either causing, or associated with an increased risk of, inherited disease [Bandiera et al, 2010;Martin et al, 2007;Rademakers et al, 2008;Sethupathy and Collins, 2008;Simon et al, 2010].…”