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
316CT
R106W
Exons
II
1
502 CT
R168X
III
26
763 CT 808 CT
R255X
R270X
IV
235
376
486
397CT
R133C
473CT
T158M
625
930
916CT
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)