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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.

SUBMITTER: Cuny H

PROVIDER: S-EPMC7035598 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Cuny Hartmut H Rapadas Melissa M Gereis Jessica J Martin Ella M M A EMMA Kirk Rosemary B RB Shi Hongjun H Dunwoodie Sally L SL

Proceedings of the National Academy of Sciences of the United States of America 20200203 7

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 <i>HAAO</i> or <i>KYNU</i>, 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 ...[more]

PMID: 32015132

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Project description:The completion of embryonic development depends, in part, on the interplay between genetic factors and environmental conditions, and any alteration during development may affect embryonic genetic and epigenetic regulatory pathways leading to congenital malformations, which are mostly incompatible with life. Oviparous reptiles, such as sea turtles, that produce numerous eggs in a clutch that is buried on the beach provide an opportunity to study embryonic mortality associated with malformations that occur at different times during development, or that prevent the hatchling from emerging from the nest. In sea turtles, the presence of congenital malformations frequently leads to mortality. A few years ago, a detailed study was performed on external congenital malformations in three species of sea turtles from the Mexican Pacific and Caribbean coasts, the hawksbill turtle, Eretmochelys imbricata (n = 23,559 eggs), the green turtle, Chelonia mydas (n = 17,690 eggs), and the olive ridley, Lepidochelys olivacea (n = 20,257 eggs), finding 63 types of congenital malformations, of which 38 were new reports. Of the three species, the olive ridley showed a higher incidence of severe anomalies in the craniofacial region (49%), indicating alterations of early developmental pathways; however, several malformations were also observed in the body, including defects in the carapace (45%) and limbs (33%), as well as pigmentation disorders (20%), indicating that deviations occurred during the middle and later stages of development. Although intrinsic factors (i.e., genetic mutations or epigenetic modifications) are difficult to monitor in the field, some environmental factors (such as the incubation temperature, humidity, and probably the status of feeding areas) are, to some extent, less difficult to monitor and/or control. In this review, we describe the aetiology of different malformations observed in sea turtle embryos, and provide some actions that can reduce embryonic mortality.

Dataset Information

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

Publications

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

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