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 individuals have recurrent molar pregnancies of diploid biparental origin. To date only a small number of affected families have been descibed. 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: Sixteen different mutations were identified in the study, thirteen 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 male with two affected sisters and homozygous for the p.R693P mutation had normal reproductive outcomes. In normal human ovary NLRP7 expression is confined to the oocytes and present at all stages from primordial to tertiary follicles.

Conclusion: Thirteen 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 observed identifies the LRR region to be critical for normal functioning of NLRP7.