title: An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders.
abstract: Mutations in the X-linked MECP2 cause Rett syndrome, a devastating neurological disorder typified by a period of apparently normal development followed by loss of cognitive and psychomotor skills. Data from rare male patients suggest symptom onset and severity can be influenced by the location of the mutation, with amino acids 270 and 273 marking the difference between neonatal encephalopathy and death, on the one hand, and survival with deficits on the other. We therefore generated two mouse models expressing either MeCP2-R270X or MeCP2-G273X. The mice developed phenotypes at strikingly different rates and showed differential ATRX nuclear localization within the nervous system, over time, coinciding with phenotypic progression. We discovered that MeCP2 contains three AT-hook-like domains over a stretch of 250 amino acids, like HMGA DNA-bending proteins; one conserved AT-hook is disrupted in MeCP2-R270X, lending further support to the notion that one of MeCP2's key functions is to alter chromatin structure.
authors: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Steven Andrew
authors: SA
authors: Baker
authors: Lin
authors: L
authors: Chen
authors: Angela Dawn
authors: AD
authors: Wilkins
authors: Peng
authors: P
authors: Yu
authors: Olivier
authors: O
authors: Lichtarge
authors: Huda Yahya
authors: HY
authors: Zoghbi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004265:DNA Helicases / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006570:Heterochromatin / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016415:Sequence Alignment; D014158:Transcription, Genetic; D000075924:X-linked Nuclear Protein
chemical_list: D006570:Heterochromatin; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D009687:Nuclear Proteins; D004265:DNA Helicases; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein