Download Holoprosencephaly

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts
no text concepts found
Transcript
What I Know Best:
Holoprosencephaly
Max Muenke
Medical Genetics Branch
National Human Genome Research Institute
National Institutes of Health
B th d M
Bethesda,
Maryland,
l d USA
[email protected]
Second European Course in Clinical Dysmorphology
Rome, March 28-29, 2008
Clinical Projects
j
• Holoprosencephaly
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
• ADHD
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
• “Muenke”
“M
k ” syndrome
d
Holoprosencephaly (HPE)
Nodal and Hedgehog Signaling
Low
L
Cholesterol
NODAL
SHH
CDO
TDGF1
DISP1
PTC
TGIF
FOXH1
SIX3
ZIC2
GLI2
Sonic Hedgehog,
Hedgehog
Cholesterol,
Brain Development,
and Prematurity
H l
Holoprosencephaly
h l (HPE)
• Midline Defect of the Developing Forebrain
and Face
• Prevalence: 1 in 250 Early Embryos
1 in 10,000
,
LiveLive-born Infants
less than 1:100,000 over 1 Y/O
• Etiology:
Extremely Heterogeneous
Alobar HPE
Semilobar HPE
Holoprosencephaly
p
p y
“The Face Predicts the Brain”
Holoprosencephaly Gene Carriers
Causes of HPE
• Cytogenetic Anomalies
• Gene Mutations
• Defects of Cholesterol Biosynthesis
• Gene/Environment
G
/E i
t Interactions
I t
ti
Causes of HPE
• Cytogenetic Anomalies
• Gene Mutations
• Defects of Cholesterol Biosynthesis
• Gene/Environment
G
/E i
t Interactions
I t
ti
Low maternal cholesterol?
Maternal diabetes?
Alcohol exposure?
p
Retinoic acid exposure?
Cytogenetic Anomalies in HPE
Positional Cloning of HPE Genes
HNF3β?
β
TGIF
ZIC2
SHH
SIX3
DISPATCHED
Microdeletion Detection by
Multicolor FISH
Dispatched
p
: 1q41
q
SIX3 :
2p21
SHH :
7q36
ZIC2 :
13q32
TGIF :
18p11
HNF3 β :
20p11
p
Microdeletion of TGIF
18
2
1
18
7
13
13
20
7
1
20
2
46,XY.ish del(18)(p11.3p11.3)(TGIF
del(18)(p11.3p11.3)(TGIF--)
Microdeletion Detection
• Multicolor FISH
• qPCR
• MLPA
• aCGH
Familial Holoprosencephaly
p
p y
Positional Cloning of HPE Genes
SHH
Sonic Hedgehog Cleavage
and Modification
Palmitate
Cholesterol
Sonic Hedgehog Cleavage
C25S
and Modification
C198X generates Shh-N without
cholesterol or C-terminus
Palmitate
Cholesterol
Sonic Hedgehog Cleavage
and Modification
Human Hedgehog
Acyltransferase
(HHAT)
Palmitate
Cholesterol
SHH Signaling
SHH Signaling
Nodal and Hedgehog Signaling
Low
L
Cholesterol
NODAL
SHH
CDO
TDGF1
DISP1
PTC
TGIF
FOXH1
SIX3
ZIC2
GLI2
Two Mutations in HPE Patients
SHH Mutations in Families with SCI
Cholesterol biosynthesis and
holoprosencephaly
Background: Pertubations of cholesterol
homeostasis are an important factor in HPE
pathogenesis in animal models
Purpose:
p
Are alterations in cholesterol biosynthesis are associated with HPE in humans?
Methods: In vitro loading test using 14C-acetate
C acetate
as a substrate which identifies C27 sterols in
lymphoblasts and comparison with GCMS
Cholesterol biosynthesis and
holoprosencephaly
Results: 22 of 230 patients (9.6%) with various
HPE phenotypes had abnormal sterol profiles
that were different from known defects
Conclusion: Impaired cholesterol biosynthesis
contributes to the etiology of HPE in humans
Future
F
t
studies:
t di
A l i off enzyme defects
Analysis
d f t that
th t
lead to the abnormal sterol patterns in HPE
patients
Summary: Causes of HPE
• Cytogenetic Anomalies:~50
Anomalies:~50--60%
• Gene Mutations:
~10
~10--15%
• Defects of Cholesterol Biosynthesis:
~ 5%
• Gene/Environment Interactions:
~30--40% (?)
~30
Holoprosencephaly
“Does
Does the Face Predict the Cause?”
Cause?
With few exceptions: NO
Facial findings in children with HPE
and ZIC2 mutations
Facial findings
in children
with
ith pituitary
it it
anomalies
and GLI2
mutations
Brain Development and Cholesterol
Maternal cholesterol in early
embryogenesis is crucial for
normal craniofacial and brain
development.
development
Modified
d from C.C. Hu
ui
Statins
Cholesterol Biosynthesis
First Trimester Statins
CNS A
Anomalies
li
HPE,, NTD
Limb Reduction
Defects
VACTERL
Brain Development and Cholesterol
•Pilot study of cholesterol
in the parents and children
with isolated HPE
Result: significantly lower
cholesterol
h l t
l in
i mothers
th
Brain Development and Cholesterol
•HPE in patients
with Smith
Smith-LemliLemli
Opitz Syndrome
(SLOS)
Acknowledgements
g
Holoprosencephaly
p
p y
Cholesterol
Clinicians around the world
Robin Edison, NIH
Kate Berg, NIH
Alan Remaley,
Remaley NIH
Erich Roessler
Roessler, NIH
Kenia El-Jaick, NIH, now UFRJ
J.P. Karkera, NIH
Claude Bendavid, NIH, U. Rennes
Maia Ouspenskaia, NIH
Roger Stevenson,
Greenwood Genetics Ctr
Jean Golding, U. Bristol, UK
Richard Kelley, KKI/JHU
Ben Feldman,
Feldman NIH
Jeff Ming, CHOP/Penn, now Merck
Bassem Haddad, Georgetown U.