The Role of NLRP Gene Family (NLRP1~14) in Recurrent Miscarriage and Infertility
Condition: Miscarriage, Recurrent; Infertility
MeSH terms: Infertility; Abortion, Spontaneous; Abortion, Habitual; Recurrence
Study type: Observational

Summary: 
      Development of mole was not associated with segregation of mutated NLRP7 allele in the
      haploid oocyte. We hypothesize NLRP7 is a maternal factor involved in regulating early embryo
      development or embryo-uterine interaction. In the proposed study, we seek to identify novel
      genetic variants and mutations of NLRP7 in women who experienced RM/HM. Genetic association
      study and haplotype analysis are performed to test assocation between NLRP7 gene and female
      reproductive performance. Immunohistochemical staining, RT-PCR, and Western blot analysis are
      used to investigate expression pattern of NLRP7 in endometrium and placenta. Two approaches
      are used to characterize functional significance of genetic variants/mutations. The first
      approach will be based on mutagenesis and the second approach will be based on induced
      pluripotent stem cells (iPSCs). Results obtained from the proposed study will provide novel
      insight into mechanism of embryo development and implantation.
    

Detailed description: 
      Recurrent miscarriage (RM), defined as at least two consecutive fetal death or spontaneous
      abortions before the 20th week gestational age, occurred in about 1% to 5% couples. The
      causes of RM include uterine factors, endocrine factors, thromobophilic factors, immunologic
      factors and genetic factors. The hydatidiform mole (HM) can be divided into two separate
      syndromes: complete mole (CHM) and partial mole (PHM). In the West, CHMs occur in
      approximately 1 in every 1500 pregnancies. The incidence is higher in Latin America,
      Southeast Asia and the Middle East. The cause of RM and HM are not known for the vast
      majority of cases. The NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat
      and Pyrin domain containing) family, also referred to as NALP family, is well known for its
      roles in apoptosis and inflammation. Expression studies showed that twelve of the fourteen
      members of NLRP family express differentially in human oocytes and preimplantation embryonic
      cells, especially NLRP7, indicating important role of NLRP family in female reproduction.
      Since 2006, mutations of NLRP7 have been found in women with repeated occurrence of molar
      pregnancy, repeated stillbirth or early spontaneous abortion. In women who experienced RM/HM,
      we also found some novel mutations/genetic variants of NLRP7. Taken together, these finding
      suggest RM and HM may share the same genetic etiology in some cases. In addition, NLRP7 is a
      strong candidate gene for RM/HM. A recent report showed chaotic cleavage abnormalities of
      embryos in patients with NLRP7 variants.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        Assuming that there are 300 cases and 300 controls enrolled, the underlying disease model
        is recessive, the disease prevalence is approximately 3% and the disease allele frequency
        is about 5%, this study has more than 80% power for detecting the SNP with an allele
        frequency greater than 10% and an allelic odds ratio greater than 1.4. We assumed that the
        SNP is either the causal gene or in LD with the causal allele and power was calculated
        without multiple testing corrections.
      
Biospecimen description: 
      DNA extracted from peripheral blood.
    
Keywords: recurrent miscarriage; infertility