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Syndrome (FXTAS)
What our children teach us
IV
Congreso
Internacional
del
Sndrome
X
Frgil
Associaci
Catalana
SXF
October 10, 2015
Paul J Hagerman MD. PhD
Professor, Department of Biochemistry
and Molecular Medicine,
Investigator, UC Davis MIND Institute
University of California, Davis, School of
Medicine
Core features
Tremor Onset in right hand at
age 54, left hand within two
years; writing illegible at 58 yr;
retired early as an electrician at
58 yr.
Ataxia Progressive difficulty
with balance and gait; frequent
falls
Gait ataxia
- Cognitive decline
- Autonomic dysfunction
- Anxiety, mood instability
- Parkinsonism
Gait ataxia
- Cognitive decline
- Autonomic dysfunction
- Anxiety, mood instability
- Parkinsonism
Ataxia
17%
Parkinsonism
24%
Tremor
20%
< 45
Full mutation
(CGG)
> 200
mRNA
FMRP
Clinical Typical
Fragile X syndrome
< 45
Premutation
(CGG)
55 - 200
Full mutation
(CGG)
> 200
mRNA
FMRP
Clinical Typical
Fragile X syndrome
Primary Ovarian Insufficiency (POI)
FXTAS
Neurodevelopmental problems
Astrocytes
inclusion
CGG
Viral promoter
CGG
FMRP coding
SK neural cells
88 CGG repeats
DAPI
crystallin
merged
crystallin
merged
Myotonic dystrophy
DMPK 3UTR
Myotonic dystrophy
DMPK 3UTR
FXTAS
FMR1 5UTR
DGCR8/DROSHA
Loss of proteins prevents
their normal function
Pur
hnRNP
A2/B1
CUGBP
Etc.
FMR1 5UTR
CGGCGGCGGCGGCGGCGGCGGCGG
DGCR8
DROSHA
DGCR8
DROSHA
DGCR8
DROSHA
CGGCGGCGGCGGCGGCGGCGGCGG
Transcription
C
G
CGGCGGCGGCGGCGGCGGCGGCGG G
DNA
DROSHA
pri-miR
DGCR8
DROSHA
pre-miR
DGCR8
DROSHA
DGCR8
mature
miRNA
DROSHA
decreased
miRNA levels
CGGCGGCGGCGGCGGCGGCGGCGG
Transcription
C
G
CGGCGGCGGCGGCGGCGGCGGCGG G
DNA
DROSHA
pri-miR
pre-miR
DGCR8
DROSHA
DGCR8
DROSHA
DGCR8
mature
miRNA
Observed decreases in
miRNA levels
1
0.75
CTL
0.50
0.25
0
FXTAS
miR-26a1
qRT-PCR
DROSHA
1
0.75
0.50
0.25
0
miR-190
Post-transcriptional
mechanisms
Protein
sequestration
Inclusion
Formation
Evidence of cellular
pathology
Ubiquitin
Merge
Post-transcriptional
mechanisms
Protein
sequestration
RAN translation
RAN
products
FMRP
Todd 2013
Inclusion
Formation
Inclusion
Formation
Evidence of cellular
pathology
Evidence of cellular
pathology
Pathogenesis of FXTAS
DNA damage response (DDR) model
C Iwahashi
nucleolus
inclusion
inclusion
Inclusion
Inclusion
Inclusion
Inclusion
Neuronal
cell death
ROS
Progressive
mitochondrial
dysfuncOon
6,13, and 20
DIV (days in vitro)
To environmental toxins
To seizures
To oxidative stress
To second genetic hits
Chen et al 2009
18 wk
34 wk
gene
on
18 wk
34 wk
gene
on
Control
18 wk
34 wk
gene
off
percentage
8 weeks gene on
Inclusion size
dox
wash-out
1.20
1.00
**
0.80
0.60
0.40
0.20
0.00
8 wks
MIND
Ins9tute
Randi
Hagerman
Louise
Gane
Jennifer
Cogswell
Patrick
Adams
Michele
Ono
Susan
Rivera
Iin
Wirnarni
Len
Abbeduto
Radiology
James Brunberg
Rehab Med
UCHSC (Denver)
Neurology
Maureen Leehey
Medicine
James Grigsby
Neurology
Christopher Goetz
Deborah Hall
Erasmus MC (Rotterdam)
Clinical
Gene9cs
Psychiatry
David
Hessl
Andreea
Seritan
Susan
Rivera
Noelle
LEtoile
Andrea
Schneider
Steve
Noctor
Chris
Cunningham
Pacific Biosciences
Jackie Yen
John Major
David Rank
John Eid
Paul Peluso
Luke Hickey
Thang Pham
Danuta Loesch
10/06/15