Advertisement

The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome

      Abstract

      A gene for Methyl-CpG binding protein 2 (MECP2), which locates Xq28, was recently found to be responsible for Rett syndrome. Although mutational analyses of MECP2 in Rett syndrome have been extensively analyzed, the mechanism(s) by which variable clinical phenotype occurred between affected monozygotic twins or sisters have not been clarified. We hypothesized that the difference of X-inactivation pattern might explain this phenomenon. With the method based on methylation-specific PCR, we analyzed polymorphic trinucleotide repeat in the human andorogen receptor gene mapped on Xq11.2-12, using DNA samples derived from previously described monozygotic twins and sisters together with their parents. Their clinical phenotypes were reported to be significantly different between siblings. We found that (1) maternally derived allele is predominantly active than paternally derived one in three out of four patients analyzed, (2) remaining one twin patient, whose ratio of active paternal allele is almost the same level as maternal allele, showed far much severe phenotype when compared with her counterpart. Together with the finding that most of the alleles with de novo mutation are from paternal X chromosome in sporadic cases, the existence of a mechanism that suppresses mutated paternal allele activation, resulting skewed X-inactivation to make clinical phenotype milder, might be speculated. Thus, when this mechanism fails to work sufficiently by an unknown reason, severer clinical phenotype could occur.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Amir R.E.
        • Van den Veyver I.B.
        • Wan M.
        • Tran C.Q.
        • Francke U.
        • Zoghbi H.Y.
        Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.
        Nat Genet. 1999; 23: 185-188
        • Cheadle J.P.
        • Gill H.
        • Fleming N.
        • Maynard J.
        • Kerr A.
        • Leonard H.
        • et al.
        Long-read sequence analysis of the MIECP2 gene in Rett syndrome patients: Correlation of disease severity with mutation type and location.
        Hum Mol Genet. 2000; 9: 1119-1129
        • Ogawa A.
        • Mitsudome A.
        • Yasumoto S.
        • Matsumoto T.
        Japanese monozygotic twins with Rett syndrome.
        Brain Dev. 1997; 19: 568-570
        • Miyamoto A.
        • Yamamoto M.
        • Takahashi S.
        • Oki J.
        Classical Rett syndrome in sisters: variability of clinical expression.
        Brain Dev. 1997; 19: 492-494
        • Amir R.E.
        • Van den Veyver I.B.
        • Schultz R.
        • Malicki D.M.
        • Tran C.Q.
        • Dahle E.J.
        • et al.
        Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes.
        Ann Neurol. 2000; 47: 670-679
        • Kubota T.
        • Nonoyama S.
        • Tonoki H.
        • Masuno M.
        • Imaizumi K.
        • Kojima M.
        • et al.
        A new assay for the analysis of X-chromosome inactivation based on methylation-specific PCR.
        Hum Genet. 1999; 104: 49-55
        • Girard M.
        • Couvert P.
        • Carrie A.
        • Tardieu M.
        • Chelly J.
        • Beldjord C.
        • et al.
        Parental origin of de novo MECP2 mutations in Rett syndrome.
        Eur J Hum Genet. 2001; 9: 231-236
        • Trappe R.
        • Laccone F.
        • Cobilanschi J.
        • Meins M.
        • Huppke P.
        • Hanefeld F.
        Engel MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin.
        Am J Hum Genet. 2001; 68: 1093-1101