title: Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome.
abstract: 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 isoforms with unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2 exon 1 mutations but not exon 2 mutations 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 and hypo-activity prior to death between 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 phosphorylated MeCP2-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.
authors.affiliation: Department of Medical Microbiology and Immunology, UC Davis, Davis, CA, USA.
authors.forename: Dag H
authors.initials: DH
authors.lastname: Yasui
authors.forename: Michael L
authors.initials: ML
authors.lastname: Gonzales
authors.forename: Justin O
authors.initials: JO
authors.lastname: Aflatooni
authors.forename: Florence K
authors.initials: FK
authors.lastname: Crary
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hu
authors.forename: Bryant J
authors.initials: BJ
authors.lastname: Gavino
authors.forename: Mari S
authors.initials: MS
authors.lastname: Golub
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
authors.forename: N
authors.initials: N
authors.lastname: Carolyn Schanen
authors.forename: Carl O
authors.initials: CO
authors.lastname: Olson
authors.forename: Mojgan
authors.initials: M
authors.lastname: Rastegar
authors.forename: Janine M
authors.initials: JM
authors.lastname: Lasalle
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005091:Exons / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics*
chemical_list: D051783:Methyl-CpG-Binding Protein 2