neurogenetics

, 10:127 | Cite as

The first missense mutation causing Rett syndrome specifically affecting the MeCP2_e1 isoform

  • Yann Fichou
  • Juliette Nectoux
  • Nadia Bahi-Buisson
  • Haydeé Rosas-Vargas
  • Benoit Girard
  • Jamel Chelly
  • Thierry Bienvenu
Original Article

Abstract

We report the identification of the first de novo mutation at a highly conserved residue within the polyalanine stretch in the N-terminal region of the brain-dominant protein isoform MeCP2_e1 in a girl with classical Rett syndrome. The missense mutation, p.Ala2Val, leads to severe developmental delay, microcephaly, no language, severe epilepsy, and cognitive impairment. To evaluate the pathogenic potentials of the MECP2 mutation specific to the MeCP2_e1 isoform detected in this patient, full-length wild-type and mutated cDNAs were cloned in eukaryotic expression vectors to generate a fusion protein with c-myc, and constructs were transfected in COS7 cells. In vitro studies demonstrated that, like wild-type MeCP2e_1, the N-terminal mutant is localized in the nucleus. Neither transcriptional nor translational effect on the MeCP2_e2 isoform was observed in fibroblasts from the p.Ala2Val patient, suggesting that MeCP2_e1 is involved in other functional process. These data suggest the important involvement of the N-terminus in the function of MeCP2 protein, and provide further evidence for the major impact of a specific MeCP2e_1 deficiency in the development of intellectual processing.

Keywords

MECP2 Rett syndrome Isoforms Missense mutation 

Notes

Acknowledgments

This work was supported by a grant of ANR-Maladies rares (ANR-6-MRAR-003-01; ANR-e-Rare EuroRETT). JN is currently funded by INSERM (Institut National la Recherche Scientifique; Poste d’acceuil).

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Yann Fichou
    • 1
    • 2
  • Juliette Nectoux
    • 1
    • 2
  • Nadia Bahi-Buisson
    • 3
  • Haydeé Rosas-Vargas
    • 1
    • 2
  • Benoit Girard
    • 4
  • Jamel Chelly
    • 1
    • 2
    • 4
  • Thierry Bienvenu
    • 1
    • 2
    • 4
    • 5
  1. 1.Institut CochinUniversité Paris DescartesParisFrance
  2. 2.InsermParisFrance
  3. 3.Assistance PubliqueHôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de NeuropédiatrieParisFrance
  4. 4.Assistance PubliqueHôpitaux de Paris, Hôpital Cochin, Laboratoire de Biochimie et Génétique MoléculaireParisFrance
  5. 5.Laboratoire de Génétique et de Physiopathologie des Maladies Neuro-développementalesInstitut CochinParisFrance

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