Background: Despite advances in the characterisation of mutations in the MECP2-coding region, a small proportion of classic RTT cases remain without recognisable mutations.
Objective and methods: To identify previously unknown mutations, a quantitative assay was established, providing estimates of MECP2_e1 and MECP2_e2 expression levels in peripheral blood. A systematic analysis of an Israeli cohort of 82 patients with classic and atypical RTT is presented, including sequence analysis of the MECP2-coding region, MLPA, XCI and quantitative expression assays.
Results and conclusion: A novel mis-sense mutation at ca 453C→T (pD151E), resulting in a change of a conserved residue at the methyl-binding domain, and a rare GT deletion of intron 1 donor splice site are reported. It is shown that various MECP2 mutations had distinct effects on MECP2 expression levels in peripheral blood. The most significant (p<0.001) reduction in the expression of both MECP2 isoforms was related to the presence of the intron 1 donor splice-site mutation. Using quantitative expression assays, it was shown that several patients with classic and atypical RTT with no mutation findings had significantly lower MECP2 expression levels. Further research on these patients may disclose still elusive non-coding regulatory MECP2 mutations.
- MECP2, methyl-CpG-binding protein 2
- MLPA, multiple ligation-dependent probe amplification
- PCR, polymerase chain reaction
- PSV, preserved speech variant
- QtPCR, quantitative PCR reaction
- RTT, Rett’s syndrome
- UTR, untranslated region
- XCI, X chromosome inactivation
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Funding: This study was supported by the Central Fund for the Development of Services for the Retarded in the Local Councils, Israel. BAM was supported by the Rett Syndrome Research Foundation and HL was supported by the Sigrid Juselius Foundation, Finland.
Competing interests: None declared.
This work is part of the requirements of the PhD thesis of YPG at the Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.