title: Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region.
abstract: BACKGROUND
  NLRP7 (NALP7) has recently been identified as the causative gene for familial recurrent hydatidiform mole (FRHM), a rare autosomal recessive condition in which affected women have recurrent molar pregnancies of diploid biparental origin. To date only a small number of affected families have been described. Our objectives were to investigate the diversity of mutations and their localisation to one or both isoforms of NLRP7, by screening a large series of women with FRHM and to examine the normal expression of NLRP7 in ovarian tissue.
  
  
  METHODS
  Fluorescent microsatellite genotyping of molar tissue was used to establish a diagnosis of FRHM. Twenty families were subsequently screened for mutations in NLRP7 using DNA sequencing. Expression of NLRP7 in the ovary was examined by immunohistochemical staining.
  
  
  RESULTS
  16 different mutations were identified in the study, 13 of which were novel. Missense mutations were found to be present in transcript variant 2 of NLRP7 and cluster in the leucine-rich region (LRR). A man with two affected sisters and homozygous for the p.R693P mutation had normal reproductive outcomes. In the normal human ovary, NLRP7 expression is confined to the oocytes and present at all stages from primordial to tertiary follicles.
  
  
  CONCLUSIONS
  13 novel mutations in NLRP7 were identified. We confirm that mutations in NLRP7 affect female but not male reproduction, and provide evidence that transcript variant 2 of NLRP7 is the important isoform in this condition. The mutation clustering seen confirms that the LRR is critical for normal functioning of NLRP7.
authors.affiliation: Institute of Reproductive and Developmental Biology, Imperial College London, London W12 0NN, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Wang
authors.forename: P H
authors.initials: PH
authors.lastname: Dixon
authors.forename: S
authors.initials: S
authors.lastname: Decordova
authors.forename: M D
authors.initials: MD
authors.lastname: Hodges
authors.forename: N J
authors.initials: NJ
authors.lastname: Sebire
authors.forename: S
authors.initials: S
authors.lastname: Ozalp
authors.forename: M
authors.initials: M
authors.lastname: Fallahian
authors.forename: A
authors.initials: A
authors.lastname: Sensi
authors.forename: F
authors.initials: F
authors.lastname: Ashrafi
authors.forename: V
authors.initials: V
authors.lastname: Repiska
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: Y
authors.initials: Y
authors.lastname: Xiang
authors.forename: P M
authors.initials: PM
authors.lastname: Savage
authors.forename: M J
authors.initials: MJ
authors.lastname: Seckl
authors.forename: R A
authors.initials: RA
authors.lastname: Fisher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D005190:Family; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics*; D007930:Leucine; D008297:Male; D018895:Microsatellite Repeats; D020125:Mutation, Missense; D010053:Ovary / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012008:Recurrence
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502448:NLRP7 protein, human; D007930:Leucine