NLRP genes and their role in preeclampsia and multi-locus imprinting disorders

Abstract

Preeclampsia (PE) affects 2-5% of all pregnancies. It is a multifactorial disease, but it has been estimated that 35% of the variance in liability of PE are attributable to maternal genetic effects and 20% to fetal genetic effects. PE has also been reported in women delivering children with Beckwith-Wiedemann syndrome (BWS, OMIM 130650), a disorder associated with aberrant methylation at genomically imprinted loci. Among others, members of the NLRP gene family are involved in the etiology of imprinting defects. Thus, a functional link between PE, NLRP gene mutations and aberrant imprinting can be assumed. Therefore we analyzed a cohort of 47 PE patients for NLRP gene mutations by next generation sequencing. In 25 fetuses where DNA was available we determined the methylation status at the imprinted locus. With the exception of one woman heterozygous for a missense variant in the NLRP7 gene (NM_001127255.1(NLRP7):c.542G>C) we could not identify further carriers, in the fetal DNA normal methylation patterns were observed. Thus, our negative screening results in a well-defined cohort indicate that NLRP mutations are not a relevant cause of PE, though strong evidence for a functional link between NLRP mutations, PE and aberrant methylation exist.

Integrated Protein Network Analysis of Whole Exome Sequencing of Severe Preeclampsia

“…There have been several sequencing efforts including whole genome, whole exome and targeted sequencing on an array of preeclampsia phenotypes from diverse populations 37,[55][56][57][58][59][60][61][62][63][64] . There is no consensus among the published results in regards to associated genes and variants.…”

NLRP7 Is Involved in the Differentiation of the Decidual Macrophages

“…NLRP7 transcripts have been detected in the endometrium, placenta, hematopoietic cells, oocytes and preimplantation embryos [29]. NLRP7 is usually referred to as a maternal effect gene, whose mutations result in miscarriage, stillbirth, fetal growth restriction, preeclampsia, and imprinting disorders [17,29,30,31,32,33,34]. NLRP7 and KHDC3L, a component of subcortical maternal complex (SCMC), have been co-localized to the oocyte cytoskeleton and became predominant at the cortical region in growing oocytes [35].…”

Gene-based analyses of the maternal genome implicate maternal effect genes as risk factors for conotruncal heart defects

“…Although MEGs have not previously been implicated as potential maternal risk factors for CTDs, studies in model systems demonstrate that mutations in MEGs can have a range of consequences for offspring, including embryonic lethality, developmental delay, and congenital malformations [11][12][13]. Similarly, women carrying a MEG mutation (e.g., NLRP5, NLRP7, and PADI6) experience a range of reproductive outcomes, including hydatidiform moles, periods of infertility, reproductive loss, offspring with multi-locus imprinting disorders, and unaffected children [43][44][45][46]. Although somewhat anecdotal, it is of interest that one (of five) woman with an NLRP5 mutation, ascertained following the birth of a child with a multi-locus imprinting disorder, also had a child with an isolated (i.e., apparently non-syndromic) CHD (atrial septal and ventricular defects) [43].…”