Mice with an isoform-ablating Mecp2exon 1 mutation recapitulate the neurologic deficits of Rett syndrome

Dag H. Yasui, Michael L. Gonzales, Justin O. Aflatooni, Florence K. Crary, Daniel J. Hu, Bryant J. Gavino, Mari S. Golub, John B. Vincent, N. Carolyn Schanen, Carl O. Olson, Mojgan Rastegar, Janine M LaSalle

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750). Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3 and 4 encodes MeCP2-e1 or MeCP2-e2 protein isoformswith unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2exon 1mutations but not exon 2mutations have been identified in RTT patients, suggesting that MeCP2-e1 deficiency is sufficient to cause RTT. As expected, genetic deletion of Mecp2 exons 3 and/or 4 recapitulates RTT-like neurologic defects in mice. However, Mecp2 exon 2 knockout mice have normal neurologic function. Here, a naturally occurring MECP2 exon 1 mutation is recapitulated in a mouse model by genetic engineering. A point mutation in the translational start codon of Mecp2 exon 1, transmitted through the germline, ablates MeCP2-e1 translation while preserving MeCP2-e2 production in mouse brain. The resulting MeCP2-e1 deficient mice developed forelimb stereotypy, hindlimb clasping, excessive grooming andhypo-activity prior to deathbetween 7 and 31 weeks. MeCP2-e1 deficient mice also exhibited abnormal anxiety, sociability and ambulation. Despite MeCP2-e1 and MeCP2-e2 sharing, 96% amino acid identity, differences were identified. A fraction of phosphorylatedMeCP2-e1 differed from the bulk of MeCP2 in subnuclear localization and co-factor interaction. Furthermore, MeCP2-e1 exhibited enhanced stability compared with MeCP2-e2 in neurons. Therefore, MeCP2-e1 deficient mice implicate MeCP2-e1 as the sole contributor to RTT with non-redundant functions.

Original languageEnglish (US)
Article numberddt640
Pages (from-to)2447-2458
Number of pages12
JournalHuman Molecular Genetics
Issue number9
StatePublished - 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology
  • Medicine(all)


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