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. 2019 Aug 19;9(1):11983.
doi: 10.1038/s41598-019-48385-w.

X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Clara Xiol  1 , Silvia Vidal  1 , Ainhoa Pascual-Alonso  1 , Laura Blasco  1 , Núria Brandi  2 , Paola Pacheco  1 , Edgar Gerotina  1 , Mar O'Callaghan  3 , Mercè Pineda  4 , Judith Armstrong  5   6   7 ; Rett Working Group
Collaborators, Affiliations

X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Clara Xiol et al. Sci Rep. .

Abstract

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Brain RNA Sanger Sequencing. cDNA analysis of brain samples. Electropherograms obtained from Sanger sequencing of frontal and occipital cortex cDNA samples. Blue peaks correspond to the C allele (WT), while red peaks correspond to the T allele (mutated), and the red box highlights the locus of the c.763C > T mutation in heterozygosis. Inactivation ratios are shown as inactivation WT:inactivation Mut.
Figure 2
Figure 2
Brain RNA qRT-PCR analysis and comparison with XCI-AS assay results. (a) cDNA analysis of brain samples. The results obtained by qRT-PCR of frontal cortex RNA samples (% of expression of each allele). The discontinuous line indicates 50% of the expression of each allele (each allele is equally present in the sample). (b) Comparison of XCI and qRT-PCR data from patients P109 and P119 with the c.763C > T mutation. Data are shown as % of activation of each X chromosome (% Active) and % RNA expression measured by qRT-PCR.
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