Sequence variants within exon 1 of MECP2 occur in females with mental retardation

Abstract

A new splice variant of the Rett syndrome gene, MECP2, was recently identified, that includes coding sequence from exon 1, and is the predominant transcript in the central nervous system. This sequence encodes polyalanine and polyglycine stretches within the N-terminal portion of MeCP2, and may confer novel functional properties to the protein. We screened autism, mental retardation (MR), and control populations for sequence variation within this region, and identified variation in approximately 1% of MR cases screened (N = 1,410). No variants were identified in the autism sample (N = 401). Most of these variants occur within a trinucleotide repeat region and result in change in number of alanine or glycine residues within the repeat stretches. We suggest some of these variants may be a relatively frequent cause of non-specific MR or developmental delay.

Brief Report: MECP2 Mutations in People Without Rett Syndrome

“…Alternate phenotypes associated with mutations in MECP2 have previously been described in a several reports, with autism, “Angelman-like” syndrome, and mental retardation amongst them (Harvey et al 2007; Carney et al 2003; Watson et al 2001; Beyer et al 2002; Kleefstra et al 2004). MECP2 mutations appear not to be a common reason to develop these disorders and the question of whether to promote routine screening for MECP2 mutations in such conditions is still a matter of debate (Ylisaukko-Oja et al 2005).…”

“…There exists a wide variability of presentation in RTT (Bebbington et al 2008), and approximately 5% of people with typical RTT do not have any identified mutation in MECP2 . Furthermore, there have been reports of other neurodevelopmental disorders associated with mutations in MECP2 , including nonsyndromic autism and Angelman-like syndrome (Carney et al 2003; Harvey et al 2007; Watson et al 2001). In this report, we further broaden the clinical spectrum of patients with MECP2 mutations.…”

The Expanding Role of MBD Genes in Autism: Identification of a MECP2 Duplication and Novel Alterations in MBD5, MBD6, and SETDB1

“…Due to the location of MECP2 on the X chromosome, mutations in females can lead to Rett syndrome while males with the same genetic changes typically present with neonatal encephalopathy [Moretti & Zoghbi, 2006]. Further investigations have demonstrated that MECP2 misregulation can lead to a wide range of clinical features including autism, Angelman-like symptoms, mental retardation with or without infantile seizures, mild learning disabilities, and schizophrenia [Carney et al, 2003;Coutinho et al, 2007;Harvey et al, 2007;Klauck et al, 2002;Lugtenberg et al, 2009;Shibayama et al, 2004;Watson et al, 2001]. Our group previously evaluated the MECP2 gene in a dataset of female autism spectrum disorder (ASD) patients and identified two mutations reported in classic Rett syndrome patients; an Arg294X mutation and a 41 base pair deletion (Leu386fs) predicted to generate a truncated protein [Carney et al, 2003].…”

Bio-collections in autism research

“…Applied to both common and rare CNVs[73]AGREBlood and lymphoblasts4714 subjects (total)1336 subjects (AGRE)CNV analysisGenes involved in Neuronal adhesion ( NLGN1, ASTN2 ) and ubiquitin pathways ( UBE3, PARK2, RFWD2, FBXO40 ) were found in ASD patients. Further evidence of NRXN1 and CNTN4 involved with ASD.[217]AGREBlood147 subjectsGenotype phenotypeSuggested relationship between polymorphism MTFR 677C → T and autism-related behaviours[218]AGREBlood and lymphoblasts693 subjects (AGRE)5878 subjects (total)CNV analysisMicroduplications and microdeletions in chromosome 16p11.2 associated with psychiatric disorders; duplications associated with schizophrenia, bipolar disorder and ASD, and deletions with ASD and other neurodevelopmental disorders[219]AGREBlood219 subjectsVariant analysis DLX1/2 and DLX5/6 gene analysis may not contribute to ASD but functional analysis of variants still worth investigation[36]AGREBlood1410 (total)401 (AGRE)Association studyNo association found for a sequence variant in mental retardation found in exon 1 of MECP gene in autism cohort[220]AGREBlood and lymphoblasts112 families(total)79 families (AGRE)Association studyA haplotype for DRD1 is found to be associated with ASD risk amongst males[221]AGREData from [222]551 subjects (AGRE)SNP analysisAnalysis of SNPs revealed variants of CD38 associated with ASD. Variants of CD38 linked to control of OXT secretion.[223]AGRELymphoblastoid cell14 subjectsGene expression analysisFirst study to show differential expression between lymphoblastoid cell lines.…”