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Hippocrates(460-360 B.C.)
Dropsy of the Uterus, mola hydatidosa
FMFSAID, Rome 2008
NLRP7 and Hydatidiform Moles
Clinical Manifestation of HMs
May include one or several of the followings:
-vaginal bleeding in the 1st trimester (in 84% of the cases),-larger than normal growth of the uterus (28%),-excessive nausea and vomiting (8%),-anaemia (4%),-hyperthyroidism,-toxaemia of pregnancy (sepsis),-and passage of grape-like tissues from the vagina.
Several Forms of HMs
Familial recurrent
Not recurrent (1/1000 pregnanciesin Western societies, but 2-10 higher elsewhere).Complex etiology
1-6% recurrent moles10-25% a 2nd reproductive wastage
Sporadic Recurrent
Rare
Karyotype and Genotype Data of CommonSporadic HMs
CHMs Diploid PHMs Triploid
80% Androgenetic 20% Biparental
monospermic dispermic
60% 20%
p13.2
p13.3
q13.3
q13.4
p13.1
p13.2
p13.3
p12
p11
q11
q12
q13.1
q13.2
q13.3
q13.4
A Maternal Recessive Locus Responsible forRHMs
~ 4.8 MbHM candidate region
Moglabey et al., Hum Mol Genet, 1999
Hypotheses: Immunological Defect
Before 1977:
-Medawar’s hypothesis: “fetus is a semi-allograft”Consensus: Immunostimulation / immunosuppressionConsensus: Maternal immunity is down regulated during pregnancy.
-Abnormal immune relationship between the motherand her fetus may underlie pathologic pregnanciesincluding androgenetic HMs - complete allograft.
After 1977:CHMs Normal zygote
Androgenetic (2n) Biparental (2n)Kaji & Ohama, Nature 1977
Supported by the work of Surani and Solter ( 1980s)
Hypotheses: Imprinting Defect
Abnormal Methylation of Imprinted Genes in BiHMs
Maternally methylated 1 BiHM 2 BiHM in sisters
PEG3 --- ---
PEG1 --- KCNQ1OT1 ---
SNRPN --- - to -- GNAS -AS ---
GNAS -XL! s normal
GNAS -1A ---
Paternally methylated
GNAS -NES P55 +++ +++ H19 normal + to ++
Ju
dson
et
al, 2
002
El-M
aarri
et a
l, 20
03
Sequencing a Total of 80 Genes to IdentifyNLRP7
Moglabey et al.,1999
D19
S924
1151
5-31
D19
S418
NA
LP5
AA
AT
1113
8
D19
S890
Sensi et al., 2000
4.8 Mb
Hodges et al., 2003
3.5 Mb
1.1 Mb
0.65 MbMurdoch et al., 2006
NLR
P7
Size
54 genes
26 genes
Reported Mutations in NLRP7
1 93 172 491 614 957
PYD
NACHT
LRR
R693PG118X
N913S
L825X
D657V
R693W
980
L750V
E710Dfs7X
c.2810+2T>G
G99X
4
3
32
3
2
Reported women with RHMs have 2 defective alleles
Conditions Associated with familial RHMs
-Spontaneous abortions (in most families)
-Stillbirths (in half of the families)
-Preeclampsia (in some of their pregnancies)
-Early neonatal deaths (in 2 families)
-Normal pregnancies with or without severe intra uterine growth restriction (NPs in several cases).
Family ProteinHeterozygous women
MoPa61 L825X 4 NP, 1 SA
MoGe2 R693W 6 NP, 1 SA
MoCh76 Glu99X 3 NP, 1 SB
Reproductive Outcomes
One Mutation in NLRP7 is a Risk Factorfor Reproductive Wastage
Role of NLRP7 in RHMs?
What causes RHMs????-Defective oocytes???-Defective maternal reproductive tract???-or both???
NLRP7 transcripts in unfertilized denudedoocytes, endometrium, & Fallopian tubes.
NLRP7, in vitro, inhibits IL-1β secretion.
Roles of Interleukin-1β
- In rabbit and mares, intrafollicular injection ofIL-1β induces ovulation, but embryos
arrest during early cleavage (Takehara, 1994; Caillaud, 2005).
- IL-1β is involved in embryo-maternal signalling, trophoblast invasion, and proliferation (several studies).
-Cause: Inflammatory and Immunological defects
-Consequence: Abnormal methylation, when & where???
In the oocytes before fertilization?Between fertilization and implantation?Post implantation and proliferation of HMs?
Revisiting the Pathology of HMs: Old andNew Schools
Imprinting Hypothesis???Major Risk Factors for Common HMs
Environmental/physiological:
-Maternal age
Genetic:
-Maternal history of spontaneous abortions
-Maternal ethnicity
Acknowledgments
Muhieddine Seoud (Lebanon)Laila Zahed (Lebanon)Batool Mazher (Pakistan)Rashmi Bagga (India)Renate Kircheisen (Germany)Philippe Coullin (France)Jianhua Qian & Xing Xie (China)
Guy Rouleau (Canada)Asangla Ao (Canada)Amira Mehio (Canada)
Rork Kuick &Samir Hanash (USA)Osman El-Maarri &Johannes Oldenburg(Germany)
Sharlene MurdochUgljesa DjuricRabia KhanCatherine DeveaultMoglabey YollaHelwani Mazen
CIHR, FRSQ, MISRI
The patients and their families
Paternally expressed SNRPN
BiC
HM
16
Abnormal Unmethylation of the Maternal SNRPN Allele in one BiHM
Nor
mal
P
M
P
M
El-Maarri et al.Hum Mol Genet, 2003
Maternally expressed NESP55
BiC
HM
9
Maternally expressed H19
Abnormal Gain of Methylation at theMaternal Alleles in BiCHMs
M
P
P
M
BiC
HM
16
P
MN
orm
alBi
CH
M 9
P
M
P
M
Nor
mal
El-Maarri et al.Hum Mol Genet, 2003
Abnormal Methylation of Imprinted Genes in BiHMsMaternally methylated 1 BiHM 2 BiHM
in sisters 2 BiHM
unrelated PEG3 --- --- ---
PEG1 --- KCNQ1OT1 ---
SNRPN --- - to -- --- GNAS -AS --- normal to +++
GNAS -XL! s normal normal
GNAS -1A --- --- to --
Paternally methyla ted
GNAS -NESP55 +++ +++ +++ in normal TP
H19 normal + to ++ normal
Juds
on e
t
al,
2002
El-
Maa
rri
et a
l, 20
03
Kou
et a
l.
2008