Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder occurring almost exclusively in females as sporadic cases. Recently, DNA mutations in the MECP2 gene have been detected in approximately 70% of patients with RTT. To explain the sex-limited expression of RTT, it has been suggested that de novo X-linked mutations occur exclusively in male germ cells resulting therefore only in affected daughters. To test this hypothesis, we have analysed 19 families with RTT syndrome due to MECP2 molecular defects. In seven informative families we have found by DHPLC a nucleotide variant which could be used to differentiate between the maternal and the paternal allele. In each subject investigated from these families, we have amplified specifically each allele and sequenced allele-specific PCR products to identify the allele bearing the mutation as well as the parental origin of each X chromosome. This approach allowed us to determine the parental origin of de novo mutations in all informative families. In five cases, the de novo MECP2 mutations have a paternal origin and in the two other cases a maternal origin. In all transitions at CpG, the de novo mutation observed was of paternal origin. The high frequency of male germ-line transmission of the mutation (71% of RTT informative cases) is consistent with a predominant occurrence of the disease in females.
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Acknowledgements
We thank the patients and their families for their contribution in this study. We also thank Genethon and Cassini banks for providing DNA samples. This work was supported mainly by the Association Française du syndrome de Rett (ASFR). This work was also supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), the Association Française contre les Myopathies (AFM), the Fondation Jerome Lejeune (FJL) and the Fondation pour la Recherche Médicale. M Girard is a France Telecom Foundation fellow.
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Girard, M., Couvert, P., Carrié, A. et al. Parental origin of de novo MECP2 mutations in Rett syndrome. Eur J Hum Genet 9, 231–236 (2001). https://doi.org/10.1038/sj.ejhg.5200618
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DOI: https://doi.org/10.1038/sj.ejhg.5200618
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