Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans

Abstract

Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.

Figure 1. Sequence analysis of mutations in NLRP5.

(a–e) mutations, sequencing electropherograms, pedigrees and key multilocus imprinting disturbance (MLID) imprinted loci from pedigrees 1–5. The mutation, nucleotide and amino-acid information is summarized for each pedigree, below this the wild-type sequence is provided (ref), followed by available parental genotypes and proband sequencing electropherograms. Filled symbols in pedigrees represent individuals with SRS–MLID (orange) BWS–MLID (blue) and clinically non-specific-MLID (green), red dots indicate those affected by pregnancy losses with black crosses indicating one or more NLRP5 mutations. For each proband a list of key MLID loci are included (the — symbol indicates hypomethylation relative to controls) (f) Diagrammatic structure of the human NLRP5 protein showing DAPIN, NACHT and leucine-rich repeat domains is aligned to the cDNA; arrows indicate the position, variant and pedigree information of each protein alterations with novel alterations in red text.