Abstract
BackgroundMutations 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.MethodsIn 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.ResultsAnalysis 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.ConclusionThese 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.
Highlights
Rett syndrome (RTT; MIM#312750) is an X-linked neurological disorder which leads to gradual slowing of neurodevelopment in females
Synonymous mutations are generally considered as nonpathogenic, and are not expected to change the protein’s function. This paradigm has been challenged in recent years, with evidence that changes in codon usage may have consequences for the efficiency and speed of translation, that, in turn, may affect protein folding and function [20,21]
We have described the functional consequences of a synonymous mutation in MECP2 exon 1, c.48C>T in a girl with a typical, albeit relatively mild form of RTT
Summary
Rett syndrome (RTT; MIM#312750) is an X-linked neurological disorder which leads to gradual slowing of neurodevelopment in females. Methyl-CpG binding protein 2 (MeCP2; MIM 300005) [1] located at Xq28, was identified as the gene responsible for RTT [2]. A splice variant of MECP2 was discovered later, namely MECP2_E1, in which exon 2 is spliced out and translation is initiated from a START codon in exon 1, resulting in a slightly larger protein with a different N-terminal [9,10] (Figure 1). The two isoforms are identical for the remainder of the protein, and both contain the MBD and TRD (Figure 1). No pathogenic synonymous MECP2 mutation has yet been identified. We investigated a de novo synonymous variant c.48C>T (p.Gly16Gly) identified in a girl presenting with a typical RTT phenotype
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