Transcript Document
IDENTIFICATION OF THE MOLECULAR MECHANISMS IN RETT SYNDROME AND RELATED DISORDERS (RTT-GENET) X Rett Syndrome • A childhood neuro-developmental disorder • Seen almost exclusively in females • Found in a variety of racial and ethnic groups worldwide • Dr. Andreas Rett (first description-1966) • Dr. Bengt Hagberg (worldwide recognition-1983) • 1/10,000-15,000 females • 99.5% sporadic :high rate of new mutations • 1/3 – 1/4 of progressive developmental disabilities in girls • ~ 10% of profound disability in females RTT variants • Onset of infantile seizures • Congenital form • Forme fruste • Late childhood regression • Preserved speech variant Genetics of the disease –Not a genetic disease Exclusion mapping –Mitochondrial inheritance –Autosomal inheritance limited expression with sex –X-linked dominant inheritance with lethality in males X chrom. Paternal Maternal “Minimal Critical Region” X Haplotype Analysis Search for the gene Minimal Critical Region Candidate gene approach Includes Xq28 a chromosome band rich in disease genes Systematic sequencing of all the genes (over 200) in Xq28 was Dr. Uta Francke (Stanford) and Dr. Huda Zoghbi (Baylor) Identification of the RTT gene After 14 years of search the RTT gene was finally identified in 1999 MECP2 (Methyl CpG binding protein 2) MeCP2 protein • 486 amino acids and 52kD. • An abundant mammalian chromosomal protein that binds to methylated CpG. • Ubiquitously expressed, more abundant in brain. • Can bind to single methyl-CpG pair (unlike MeCP1 which requires >10 methyl-CpGs to bind DNA) • Contains four functional domains: – – – – A methyl-CpG binding domain(MBD) A transcriptional repression domain (TRD) Nuclear localization signal (NLS) C-terminal segment Potentially involved in global gene silencing. Interaction of MeCP2 protein with HDAC MECP2 mutations identified Recurrent MECP2 mutations 316CT R106W Exons II 1 502 CT R168X III 26 763 CT 808 CT R255X R270X IV 235 376 486 397CT R133C 473CT T158M 625 930 916CT R306C 880 C T R294X 1461 Important! Rett Syndrome is the first human disease found to be caused by defects in a protein involved in regulation of gene expression through its interaction with methylated DNA. A highly likely scenario on the consequences of MECP2 mutations. trc MeCP2 Methylated promoter ? Mutated MeCP2 Methylated promoter Transcriptional silencing Transcriptional noise Important issues • Identification of downstream genes regulated by MECP2 • MECP2 mutations and epigenetics • X-inactivation • Genomic imprinting • Animal models • Using conditional knock-out technology, mice that lack MECP2 either in all tissues or selectively in brain was generated (Bird et al., 2001, Guy et al. 2001). • Cellular defects associated with MeCP2 deficiency in mouse CNS? • Behavioral defects in mice? • Drugs, gene therapy, stem cells with normal MECP2 can be the solution for treatment of RTT Male Cases A %T allele %C allele 56 41 36 (50-64) (36-47) (28-43) 44 59 64 (36-50) (53-64) (57-72)