A synonymous change, p.Gly16Gly in MECP2 Exon 1, causes a cryptic splice event in a Rett syndrome patient

Abstract

Background: Mutations in MECP2 are the main cause of Rett Syndrome. To date, no pathogenic synonymous MECP2 mutation has yet been identified. Here, we investigated a de novo synonymous variant c.48C>T (p.Gly16Gly) identified in a girl presenting with a typical RTT phenotype. Methods. In silico analyses to predict the effects of sequence variation on mRNA splicing were employed, followed by sequencing and quantification of lymphocyte mRNAs from the subject for splice variants MECP2-E1 and MECP2-E2. Results: Analysis of mRNA confirmed predictions that this synonymous mutation activates a splice-donor site at an early position in exon 1, leading to a deletion (r.[=, 48-63del]), codon frameshift and premature stop codon (p.Glu17Lysfs*16) for MECP2-E1. For MECP2-E2, the same premature splice site is used, but as this is located in the 5′untranslated region, no effect on the amino acid sequence is predicted. Quantitative analysis that specifically measured this cryptic splice variant also revealed a significant decrease in the quantity of the correct MECP2-E1 transcript, which indicates that this is the etiologically significant mutation in this patient. Conclusion: These findings suggest that synonymous variants of MECP2 as well as other known disease genes - and de novo variants in particular - should be re-evaluated for potential effects on splicing. © 2013 Sheikh et al.; licensee BioMed Central Ltd.