NAD deficiency due to environmental factors or gene–environment interactions causes congenital malformations and miscarriage in mice

Abstract

Causes for miscarriages and congenital malformations can be genetic, environmental, or a combination of both. Genetic variants, hypoxia, malnutrition, or other factors individually may not affect embryo development, however, they may do so collectively. Biallelic loss-of-function variants in HAAO or KYNU, two genes of the nicotinamide adenine dinucleotide (NAD) synthesis pathway, are causative of congenital malformation and miscarriage in humans and mice. The variants affect normal embryonic development by disrupting the synthesis of NAD, a key factor in multiple biological processes, from its dietary precursor tryptophan, resulting in NAD deficiency. This study demonstrates that congenital malformations caused by NAD deficiency can occur independent of genetic disruption of NAD biosynthesis. C57BL/6J wild-type mice had offspring exhibiting similar malformations when their supply of the NAD precursors tryptophan and vitamin B3 in the diet was restricted during pregnancy. When the dietary undersupply was combined with a maternal heterozygous variant in Haao, which alone does not cause NAD deficiency or malformations, the incidence of embryo loss and malformations was significantly higher, suggesting a gene–environment interaction. Maternal and embryonic NAD levels were deficient. Mild hypoxia as an additional factor exacerbated the embryo outcome. Our data show that NAD deficiency as a cause of embryo loss and congenital malformation is not restricted to the rare cases of biallelic mutations in NAD synthesis pathway genes. Instead, monoallelic genetic variants and environmental factors can result in similar outcomes. The results expand our understanding of the causes of congenital malformations and the importance of sufficient NAD precursor consumption during pregnancy.

Maternal iron deficiency perturbs embryonic cardiovascular development

“…The induction of identical phenotypes in different individuals by genetic, environmental or gene-environment interaction is called phenocopying. This has previously been suggested to occur in some types of human congenital abnormalities, for example congenital NAD deficiency disorder 79,80 . Our results suggest that some cases of CHD or craniofacial defects might arise from maternal mutations in the almost 40 genes required for iron transport and/or metabolism.…”

Targeting energy pathways in kidney disease: the roles of sirtuins, AMPK, and PGC1α

“…It is interesting that the de novo NAD þ biosynthetic pathway only accounts for roughly 10% of total NAD þ production, 130 yet in AKI, that pathway is specifically downregulated to a degree that becomes clinically relevant. Likewise, mutations in this otherwise minor pathway have been linked to renal developmental anomalies, [131][132][133] while mutations in nicotinamide mononucleotide adenylyltransferase 1 of the salvage pathway are not associated with renal anomalies despite that pathway's more significant contribution to NAD þ stores and other clinical findings in those patients consistent with NAD þ coactivator-1a (PGC1a) regulation of nicotinamide adenine dinucleotide (NAD) biosynthesis. NAD þ is metabolized through 3 pathways.…”

Complementary and Alternative Medicine for Threatened Miscarriage: Advantages and Risks

“…Vitamin B12 supplementation has been shown to 14 Evidence-Based Complementary and Alternative Medicine lead to successful pregnancy in 80% of women with vitamin B12 deficiency [170]. Deficiency in the conversion of vitamin B3 into nicotinamide adenine dinucleotide causes congenital malformations and miscarriages in mouse models, and vitamin B3 supplementation has been shown to prevent miscarriages and birth defects [171,172]. However, recent reviews of the literature indicate that there is insufficient evidence for the benefits and harms of routine vitamin B supplementation in humans for threatened miscarriage.…”