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Lost in translation: translational interference from a recurrent mutation in exon 1 of MECP2
  1. A Saxena1,
  2. D de Lagarde1,
  3. H Leonard2,
  4. S L Williamson3,
  5. V Vasudevan3,
  6. J Christodoulou3,
  7. E Thompson4,
  8. P MacLeod5,
  9. D Ravine6
  1. 1Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Perth, Australia
  2. 2Telethon Institute of Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Australia
  3. 3Western Sydney Genetics Program, Children’s Hospital at Westmead, and Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia
  4. 4Genetics Services of South Australia, Women’s and Children’s Hospital, Adelaide, Australia
  5. 5Department of Biology, Centre for Biomedical Research, University of Victoria, Victoria, BC, Canada
  6. 6Western Australian Institute for Medical Research, Centre for Medical Research and School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
  1. Correspondence to:
 Professor David Ravine
 Western Australian Institute for Medical Research, Centre for Medical Research and School of Medicine and Pharmacology, University of Western Australia, Level 2, North Block, Royal Perth Hospital, Perth 6000, WA, Australia; ravine{at}


Background: Rett syndrome (RTT) is an X linked neuro-developmental disorder affecting mostly girls. Mutations in the coding region of MECP2 are found in 80% of classic RTT patients. Until recently, the region encoding MECP2 was believed to comprise exons 2, 3, and 4 with the ATG start site located at the end of exon 2 (MeCP2_e2).

Methods: Recent reports of another mRNA transcript transcribed from exon 1 (MeCP2_e1) prompted us to screen exon 1 among RNA samples from 20 females with classic or atypical RTT.

Results: A previously reported 11 base pair deletion in exon 1 was detected in one subject with a milder phenotype. Although RNA expression for both protein isoforms was detected from the mutant allele, evaluation of MeCP2 protein in uncultured patient lymphocytes by immunocytochemistry revealed that MeCP2 protein production was restricted to only 74–76% of lymphocytes. X chromosome inactivation studies of genomic DNA revealed similar XCI ratios at the HUMARA locus (73:27 with HpaII and 74:26 with McrBC). We have demonstrated that translation but not transcription of the MeCP2_e2 isoform is ablated by the 11 nucleotide deletion, 103 nucleotides upstream of the e2 translation start site.

Conclusions: These findings reveal that nucleotides within the deleted sequence in the 5′-UTR of the MeCP2_e2 transcript, while not required for transcription, are essential for translation.

  • 5′-UTR
  • MeCP2
  • MECP2
  • Rett syndrome
  • RNA secondary structure

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  • Published Online First 12 September 2005

  • The authors would like to acknowledge the Raine Foundation and Rett Syndrome Australian Research Fund for funding of this project as well as the National Institute of Child Health and Human Development for its current funding of the Australian Rett Syndrome Database under NIH grant number 1 R01 HD43100-01A1 PI. InterRett is funded by the International Rett Syndrome Association. DR is supported by a grant from the University of Western Australia, HL is funded by NHMRC program grant 353514, and JC is funded by NHMRC project grants 185202 and 346603.

  • Competing interests: none declared

  • Patient details are published with consent