NLRP7 and Hydatidiform Moles

Transcription

1 NLRP7 and Hydatidiform Moles Hippocrates ( B.C.) Dropsy of the Uterus, mola hydatidosa FMFSAID, Rome 2008

2 Clinical Manifestation of HMs

3 Ultrasound and Gross Morphology of a Complete Hydatidiform Mole Histopathology CHM PHM

4 Several Forms of HMs Sporadic Recurrent 1-6% recurrent moles 10-25% a 2 nd reproductive wastage Familial recurrent Not recurrent (1/1000 pregnancies in Western societies, but 2-10 higher elsewhere). Complex etiology Rare

5 Karyotype and Genotype Data of Common Sporadic HMs CHMs Diploid PHMs Triploid 80% Androgenetic 20% Biparental 60% 20% monospermic dispermic

6 Karyotype and Genotype Data of RHMs RHMs Mostly biparental, some androgenetic All biparental

7 A Maternal Recessive Locus Responsible for RHMs p13.3 p13.2 p13.3 p13.2 p13.1 p12 p11 q11 q12 q13.1 HM candidate region ~ 4.8 Mb q13.2 q13.3 q13.4 q13.3 q13.4 Moglabey et al., Hum Mol Genet, 1999

8 Hypotheses: Immunological Defect Before 1977: -Medawar s hypothesis: fetus is a semi-allograft Consensus: Immunostimulation / immunosuppression Consensus: Maternal immunity is down regulated during pregnancy. -Abnormal immune relationship between the mother and her fetus may underlie pathologic pregnancies including androgenetic HMs - complete allograft.

9 Hypotheses: Imprinting Defect After 1977: CHMs Normal zygote Androgenetic (2n) Kaji & Ohama, Nature 1977 Biparental (2n) Supported by the work of Surani and Solter ( 1980s)

10 Abnormal Methylation of Imprinted Genes in BiHMs Maternally methylated 1 BiHM 2 BiHM in sisters PEG PEG1 --- KCNQ1OT1 --- SNRPN to -- GNAS -AS --- GNAS -XL! s normal GNAS -1A --- Paternally methylated GNAS -NES P H19 normal + to ++ Judson et al, 2002 El-Maarri et al, 2003

11 Abnormal Methylation at Imprinted Genes is Restricted to their DMRs Djuric et al., Hum Genet, 2006

12 Normal Postzygotic DNA Methylation at Repetitive Elements Djuric et al., Hum Genet, 2006

13 Normal Methylation at Inactive and Active X Genes Djuric et al., Hum Genet, 2006

14 Sequencing a Total of 80 Genes to Identify NLRP7 D19S NLRP7 D19S418 NALP5 AAAT11138 D19S890 Size Moglabey et al.,1999 Sensi et al., 2000 Hodges et al., genes 4.8 Mb 3.5 Mb 1.1 Mb Murdoch et al., Mb 26 genes

15 Reported Mutations in NLRP7 E710Dfs7X 4 G99X G118X R693P R693W D657V L750V 3 L825X 2 N913S c t>g PYD NACHT Reported women with RHMs have 2 defective alleles LRR

16 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).

17 Interobserver & Intraobserver Variations C: Complete, P: partial, A: abortion

18 One Mutation in NLRP7 is a Risk Factor for Reproductive Wastage Family Protein Reproductive Outcomes Heterozygous women MoPa61 L825X 4 NP, 1 SA MoCh76 Glu99X 3 NP, 1 SB MoGe2 R693W 6 NP, 1 SA

19 Role of NLRP7 in RHMs? What causes RHMs???? -Defective oocytes??? -Defective maternal reproductive tract??? -or both??? NLRP7 transcripts in unfertilized denuded oocytes, endometrium, & Fallopian tubes. NLRP7, in vitro, inhibits IL-1β secretion.

20 Roles of Interleukin-1β - In rabbit and mares, intrafollicular injection of IL-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).

21 Revisiting the Pathology of HMs: Old and New Schools -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?

22 Imprinting Hypothesis??? Major Risk Factors for Common HMs Environmental/physiological: -Maternal age Genetic: -Maternal history of spontaneous abortions -Maternal ethnicity

23 Areas of low incidence Areas of high incidence

24 Reported families with RHMs ** * * * * * * * ** * * ** * * * * * * ** * * *

25 Acknowledgments The patients and their families Sharlene Murdoch Ugljesa Djuric Rabia Khan Catherine Deveault Moglabey Yolla Helwani Mazen Guy Rouleau (Canada) Asangla Ao (Canada) Amira Mehio (Canada) Muhieddine Seoud (Lebanon) Laila Zahed (Lebanon) Batool Mazher (Pakistan) Rashmi Bagga (India) Renate Kircheisen (Germany) Philippe Coullin (France) Jianhua Qian & Xing Xie (China) CIHR, FRSQ, MISRI Rork Kuick &Samir Hanash (USA) Osman El-Maarri &Johannes Oldenburg (Germany)

26 Abnormal Unmethylation of the Maternal SNRPN Allele in one BiHM Paternally expressed SNRPN BiCHM 16 M P Normal M P El-Maarri et al.hum Mol Genet, 2003

27 Abnormal Gain of Methylation at the Maternal Alleles in BiCHMs Maternally expressed NESP55 Maternally expressed H19 BiCHM 9 Normal M P M P Normal BiCHM 16 BiCHM 9 M P M P M P El-Maarri et al.hum Mol Genet, 2003

28 Abnormal Methylation of Imprinted Genes in BiHMs Maternally methylated 1 BiHM 2 BiHM 2 BiHM in sisters unrelated PEG PEG1 --- KCNQ1OT1 --- SNRPN to GNAS -AS --- normal to +++ GNAS -XL! s normal normal GNAS -1A to -- Paternally methyla ted GNAS -NESP in normal TP H19 normal + to ++ normal Judson et al, 2002 El-Maarri et al, 2003 Kou et al. 2008

29 Age-related incidence of HMs >45

30