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.
Highlights
Rett syndrome (RTT, OMIM #312750) is a severe neurodevelopmental disorder characterized by a period of normal development until 6-18 months of age followed by a regression of neurological traits
There are some atypical RTT variants, such as the early onset seizure variant and the congenital variant, which have been associated with mutations in cyclin-dependent kinase-like 5 (CDKL5; Xp22; OMIM *300203) and forkhead box protein G1 (FOXG1; 14q12; OMIM *164874), respectively[7,8]
Since methyl-CpG binding protein 2 (MECP2) is located on the X chromosome, the severity of RTT could be theoretically regulated by X chromosome inactivation (XCI), showing a more severe phenotype as more cells express the mutated MECP214
Summary
Rett syndrome (RTT, OMIM #312750) is a severe neurodevelopmental disorder characterized by a period of normal development until 6-18 months of age followed by a regression of neurological traits. The association of RTT with mutations in methyl-CpG binding protein 2 (MECP2; Xq28; OMIM *300005) gene was recognized in 19992. More than 800 different mutations in MECP2 have been identified in more than 95% of patients with classic RTT5,6. Type of mutation Missense Missense Nonsense Missense Nonsense Frameshift Nonsense Nonsense Missense Deletion — MeCP2 region MBD MBD IDR TRD TRD TRD-NLS TRD-NLS TRD TRD Exons 3-4 —. These clinical differences have been attributed, at least in part, to X chromosome inactivation (XCI). Since MECP2 is located on the X chromosome, the severity of RTT could be theoretically regulated by XCI, showing a more severe phenotype as more cells express the mutated MECP214
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