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RETT SYNDROME. UNDERSTANDING THE ROLE OF MECP2 BASIC NEUROSCIENCE NBL 120 DECEMBER 2007. OUTLINE. CLINICAL BACKGROUND MOLECULAR IMPLICATIONS PHENOTYPE-GENOTYPE RELATION FUNCTIONAL EFFECT OF MUTATIONS. RETT SYNDROME A NEURODEVELOPMENTAL DISORDER OF YOUNG FEMALES CHARACTERIZED BY.

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rett syndrome

RETT SYNDROME

UNDERSTANDING THE ROLE OF MECP2

BASIC NEUROSCIENCE NBL 120

DECEMBER 2007

outline
OUTLINE
  • CLINICAL BACKGROUND
  • MOLECULAR IMPLICATIONS
  • PHENOTYPE-GENOTYPE RELATION
  • FUNCTIONAL EFFECT OF MUTATIONS
rett syndrome a neurodevelopmental disorder of young females characterized by
RETT SYNDROMEA NEURODEVELOPMENTAL DISORDER OF YOUNG FEMALES CHARACTERIZED BY
  • PROFOUND COGNITIVE IMPAIRMENT
  • COMMUNICATION DYSFUNCTION
  • STEREOTYPIC MOVEMENTS
  • PERVASIVE GROWTH FAILURE
rett syndrome consensus criteria 2001
RETT SYNDROME CONSENSUS CRITERIA - 2001
  • Normal at birth
  • Apparently normal early development (may be delayed from birth)
  • Postnatal deceleration of head growth in most
  • Lack of achieved purposeful hand skills
  • Psychomotor regression: Emerging social withdrawal, communication dysfunction, loss of learned words, and cognitive impairment
  • Stereotypic movements: Hand washing/wringing/squeezing; Hand clapping/tapping/rubbing; Hand mouthing
  • Gait dysfunction: Impaired (dyspraxic) or failing locomotion
rett syndrome temporal profile
RETT SYNDROME TEMPORAL PROFILE
  • APPARENTLY NORMAL DEVELOPMENT
  • ARREST OF DEVELOPMENTAL PROGRESS
  • FRANK REGRESSION WITH POOR SOCIAL CONTACT AND FINGER SKILLS
  • STABILIZATION: BETTER SOCIAL CONTACT AND EYE GAZE, BUT GRADUAL SLOWING OF MOTOR FUNCTIONS
rett syndrome what do we know
RETT SYNDROMEWHAT DO WE KNOW?
  • GENETIC DISORDER AFFECTING FEMALES PREDOMINANTLY
  • OCCURRENCE >>99.9% SPORADIC
  • VARIABLE CLINICAL EXPRESSION
  • PERVASIVE GROWTH FAILURE
  • SIGNIFICANT LONGEVITY
  • CONSISTENT NEUROPATHOLOGY
  • MORE THAN 95% OF FEMALES MEETING CONSENSUS CRITERIA HAVE MUTATIONS IN MECP2
rett syndrome in usa irsa case registry by state may 2007
Rett Syndrome in USAIRSA Case Registry by State (May 2007)

18

87

14

13

89

19

10

90

11

64

27

9

31

179

222

24

103

193

27

178

87

170

26

34

44

40

45

66

24

42

107

142

377

5

50

66

33

101

20

90

56

53

25

43

53

61

1

232

7

180

TOTAL 3712

14

Puerto Rico

10

Puerto Rico 10

rett syndrome variable clinical expression
RETT SYNDROMEVARIABLE CLINICAL EXPRESSION
  • PHENOTYPIC EXPRESSIONS
  • SEIZURES OR BEHAVIORAL PATTERNS
  • BREATHING IRREGULARITIES
  • SLEEP CHARACTERISTICS
  • SCOLIOSIS
  • AMBULATION
longevity in rett syndrome
LONGEVITY IN RETT SYNDROME
  • SURVIVAL FOLLOWS THAT OF ALL FEMALES UNTIL AGE 10
  • 70% SURVIVAL TO AGE 35 COMPARED TO 98% IN ALL FEMALES AND 27% IN PERSONS WITH PROFOUND MOTOR AND COGNITIVE IMPAIRMENT
rett syndrome brain morphology
RETT SYNDROMEBRAIN MORPHOLOGY
  • REDUCED BRAIN WEIGHT
  • REDUCED VOLUME OF SPECIFIC REGIONS
  • REDUCED MELANIN PIGMENTATION
  • SMALL NEURONS; SIMPLIFIED DENDRITES WITH REDUCED SPINES
  • ABSENCE OF RECOGNIZABLE DISEASE
other neurodevelopmental disorders
OTHER NEURODEVELOPMENTAL DISORDERS
  • DOWN SYNDROME
    • REDUCED DENDRITIC BRANCHES AND SPINES AFTER EARLY INFANCY
  • AUTISM
    • INCREASED PACKING DENSITY
    • DECREASED CELL SIZE
  • ANGELMAN AND FRAGILE X SYNDROMES:
    • REDUCED DENDRITIC ARBORIZATIONS AND SPINES
slide16

Spine Dysgenesis in Mental Retardation

Normal DS MR FraX

FMR1 KO mice

wt

Rett Syndrome

  • Down’s Syndrome (Huttenlocher ‘70, ‘74; Marin-Padilla ‘72, ‘76; Purpura ‘74, ‘75); Fragile X Syndrome - and FMR1 KO mice (Wisniewski ‘85; Greenough ‘97); Rett Syndrome (Balichenko ‘94)
rett syndrome is caused by mutations in x linked mecp2 encoding methyl cpg binding protein 2

Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

Ruthie E. Amir, Ignatia B. van den Veyver, Mimi Wan, Charles Q. Tran, Uta Francke & Huda Y. Zoghbi Nature Genet 1999;23:185

methyl cpg binding protein 2
METHYL-CpG-BINDING PROTEIN 2
  • ONE OF FAMILY OF METHYL-BINDING PROTEINS
  • CAPABLE OF TRANSCRIPTIONAL SILENCING OR REGULATION
  • UBIQUITOUS IN MAMMALIAN TISSUES
  • HIGHLY EXPRESSED IN MAMMALIAN BRAIN
  • SPECIFIC TARGET GENES UNDEFINED
  • MAY FUNCTION IN MAINTENANCE OF DEVELOPING AND MATURE NEURONS
mecp2 distribution in human brain during development
MeCP2 DISTRIBUTION IN HUMAN BRAIN DURING DEVELOPMENT
  • CAUDAL-ROSTRAL GRADIENT OF MeCP2 IN HUMAN BRAIN
  • CORTICAL NEURONS LAST TO EXPRESS

Shahbazian et al. Hum Mol Genet 2002;11:115

slide20

MeCP2

HDAC

Sin3A

Function of MeCP2

TRD

MBD

Methylated CpG

Chromatin

slide21

HDAC

Sin3A

Mutated MeCP2

MeCP2

Methylated CpG

Chromatin

what do we know about mecp2 and rett syndrome
WHAT DO WE KNOW ABOUT MECP2 AND RETT SYNDROME?
  • >95% OF CLASSIC RETT SYNDROME CAUSED BY MUTATIONS IN MECP2
  • 8 MUTATIONS ACCOUNT FOR ~ 65% OF THOSE IN RETT SYNDROME
  • SPORADIC RS: MAJORITY APPEAR TO BE OF PATERNAL ORIGIN
  • FAMILIAL RS (<<1% of total) MAJORITY DUE TO LARGE DELETION
mutations
Mutations
  • Mutations in MeCP2 found in 70-95% “classical” Rett syndrome
  • Missense, nonsense, frameshift, large scale rearrangements
does mutation predict outcome
DOES MUTATION PREDICT OUTCOME?
  • Certain mutations (R133C, R294X, and R306C and C-terminal truncations are associated with “better outcome”
    • Lower severity scores
    • Slower progression
    • Preserved speech variants
  • Missense mutations in C-terminal region in males associated with XLMR
rett syndrome and mecp2
RETT SYNDROME AND MECP2
  • RETT SYNDROME IS A CLINICAL DIAGNOSIS
  • RETT SYNDROME IS NOT SYNONYMOUS WITH MECP2 MUTATIONS
  • RETT SYNDROME MAY BE SEEN WITHMECP2 MUTATIONS
  • RETT SYNDROME MAY BE SEEN WITHOUTMECP2 MUTATIONS
  • MECP2 MUTATIONS MAY BE SEEN WITHOUT RETT SYNDROME
rett syndrome and normal mecp2
RETT SYNDROME AND NORMAL MECP2
  • LARGE SCALE DELETIONS MISSED BY CURRENT PCR METHODS
  • ALTERNATE SPLICE VARIANT, TERMED MeCP2B
  • OTHER GENES INCLUDING MeCP2 DOWNSTREAM TARGETS

Mnatzakanian et al. Nature Genet 2004;36:339-341

rett syndrome female phenotypes with mecp2 mutations
Rett SyndromeFemale Phenotypes With MECP2 Mutations
  • Rett Syndrome
  • Preserved Speech Variant
  • Delayed Onset Variant
  • Congenital Onset Variant
  • Early Onset Seizure Variant
  • Autistic-like Variant
  • Angelman Syndrome
  • Mild Learning Disability
  • Normal Carriers
rett syndrome male phenotypes with mecp2 mutations
Rett SyndromeMale Phenotypes With MECP2 Mutations
  • Fatal Encephalopathy
  • Rett/Klinefelter Syndrome
  • X-Linked MR/Progressive Spasticity
  • Somatic Mosaicism/NDD
  • MECP2 Duplications and X-linked MR
who should have mecp2 testing
WHO SHOULD HAVE MECP2 TESTING?
  • FEMALES WITH TYPICAL AND VARIANT RETT SYNDROME FEATURES
  • INFANTS, ESPECIALLY MALES, WITH UNEXPLAINED PROGRESSIVE ENCEPHALOPATHY
  • MALES WITH RETT SYNDROME FEATURES
  • CHILDREN WITH ANGELMAN FEATURES AND NORMAL METHYLATION
  • CHILDREN WITH FAMILIAL XLMR AND NORMAL FRAGILE X TESTING
assessing function of mutant protein
Assessing function of mutant protein
  • Drosophila S cells
    • Not highly methylated
  • Transfect MeCP2 construct and methylated reporter plasmid
  • Assess transcription

MeCP2

mmm

CAT

mutations decrease mecp2 repression in drosophila cells
Mutations decrease MeCP2 repression in Drosophila cells
  • Transient transfection
  • MeCP2 construct
  • CAT reporter

Relative CAT activity (%)

Kudo et al., Brain and Dev 2001

slide32

A photobleaching technique to study protein movement in living cells

Immobile fraction

T1/2

Mobile fraction

FRAP = fluorescence recovery after photobleaching

Phair RD, and Misteli T. (2001) Nat Rev Mol Cell Biol. 2(12):898-907

mouse models
MOUSE MODELS
  • Knock-out mouse: Mecp2 deleted
  • Knock-in mouse: Insertion of human mutation in Mecp2
knock out mutant
KNOCK-OUT MUTANT
  • Note

hind-limb clasping

Guy et al.

Nature Genetics 2001;27:322-326

knock out mutant1
KNOCK-OUT MUTANT
  • Is Mecp2 knock-out reversible?
  • Using estrogen receptor controlled Mecp2 promoter:
    • Mecp2 knock-out phenotype reversed in both immature male and mature male and female mice with estrogen analog, tamoxifen
    • Rapid re-expression in immature males resulted in death in 50%
          • Guy et al. Science 2007;315:1143-1147
knock in mutant
KNOCK-IN MUTANT
  • Note humped back and forelimb clasping

Young and Zoghbi, Am J Hum Genet 2004;74:511-520

knock in mutant1
KNOCK-IN MUTANT
  • Impaired hippocampus-dependent social, spatial, and contextual fear memory
  • Impaired long-term potentiation and depression
  • Reduced post-synaptic densities
  • No change in BDNF expression

Moretti et al. J Neurosci 2006;26:319-327

knock in mutant2
KNOCK-IN MUTANT
  • Enhanced anxiety and fear based on:
    • Elevated blood corticosterone levels
    • Elevated corticotropin-releasing hormone in hypothalamus, central nucleus of amygdala, and bed nucleus of stria terminalis
    • MeCP2 binds to Crh promoter methylated region
          • McGill et al. PNAS 2006;103:18267-18272
knock in mutant3
KNOCK-IN MUTANT
  • Implications of Crh over-expression:
    • Anxiety plays central role in clinical RS
    • Amygdala has direct input into hypothalamus and brainstem autonomic nuclei correlating with clinical problems of respiration, GI function, and peripheral sympathetic NS
    • Suggests strategies for therapeutic intervention
longevity study
Longevity Study
  • Data gathered on 1928 girls and women
  • Completion of data gathering and filling in missing data consumed most of winter
  • Analysis of longevity underway
  • Databank very informative
  • Appears representative
database resources
DATABASE RESOURCES
  • RettBase: Dr. John Christodoulou
    • MECP2 Mutation Repository
    • mecp2.chw.edu.au
  • InterRett: Dr. Helen Leonard
    • Clinical information repository from parents and physicians
    • www.ichr.uwa.edu.au
acknowledgements
IRSA

UAB

Jane Lane

Suzie Geerts

Jerry Childers

duPont Hospital for Children

Carolyn Schanen

NIH

NICHD/ORD/NCRR

Greenwood Genetic Center

Steve Skinner

Fran Annese

Baylor College of Medicine

Daniel Glaze

Jeff Neul

Huda Zoghbi

Judy Barrish

Girls and women with RS and their families

Acknowledgements