title: Mutation analysis of the HDAC 1, 2, 8 and CDKL5 genes in Rett syndrome patients without mutations in MECP2.
abstract: Mutations in the MECP2 gene are found in only 80% of patients with Rett syndrome (RTT). Therefore other genes have to be involved in the pathogenesis of RTT. By using our defined diagnostic criteria we first re-evaluated 50 girls with possible RTT in whom the sequencing of the MECP2 gene had not revealed any mutations. Only 15 of theses patients fulfilled all criteria for RTT and could be considered to have classical RTT. In eight of these, further molecular analyses revealed large deletions of the MECP2 gene. In the remaining seven girls we then analyzed the genes HDAC1, HDAC2, and HDAC8 that encode for the histone deacetylases 1, 2, and 8 which interact with MeCP2 and are essential for its function. Although these histone deacetylase genes have been considered as good candidate genes for RTT our molecular analysis of these genes did not detect any mutations. Because recently mutations in CDKL5 were reported in patients with RTT, we included this gene in our analysis but failed to detect any mutations. We conclude that only a subgroup of girls with possible RTT and no detectable mutation in the sequencing of the MECP2 gene do really have classical RTT. In many of those large MECP2 gene deletions can be detected by further analysis. The genes HDAC1, HDAC2, and HDAC8 do not seem to play a role in the pathogenesis of RTT and at least in our subgroup no mutations in the CDKL5 gene were detected.
authors.affiliation: Department of Pediatrics and Pediatric Neurology, Faculty of Medicine, Georg August University, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany. phuppke@med.uni-goettingen.de
authors.forename: Peter
authors.initials: P
authors.lastname: Huppke
authors.forename: Andreas
authors.initials: A
authors.lastname: Ohlenbusch
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brendel
authors.forename: Franco
authors.initials: F
authors.lastname: Laccone
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics*
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; C110550:HDAC1 protein, human; C409470:HDAC8 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases