Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3738-3747. doi: 10.1073/pnas.1916588117. Epub 2020 Feb 3.
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 or , 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 , 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.
流产和先天性畸形的原因可能是遗传的、环境的，或者两者的结合。遗传变异、缺氧、营养不良或其他因素单独可能不会影响胚胎发育，但它们可能会共同影响。在人类和小鼠中，编码烟酰胺腺嘌呤二核苷酸 (NAD) 合成途径的两个基因 和 的双等位基因失活变体是导致先天性畸形和流产的原因。这些变体通过破坏从饮食前体色氨酸合成 NAD 的过程来影响正常胚胎发育，NAD 是多种生物过程的关键因素，从而导致 NAD 缺乏。本研究表明，由 NAD 缺乏引起的先天性畸形的发生可以独立于 NAD 生物合成的遗传破坏。当 C57BL/6J 野生型小鼠在怀孕期间饮食中色氨酸和维生素 B3 的 NAD 前体供应受到限制时，它们的后代会出现类似的畸形。当饮食不足与母体杂合变体 相结合时，即使单独变体 不会导致 NAD 缺乏或畸形，胚胎丢失和畸形的发生率也会显著增加，表明存在基因-环境相互作用。母体和胚胎的 NAD 水平不足。轻度缺氧作为一个额外的因素使胚胎结局恶化。我们的数据表明，NAD 缺乏作为胚胎丢失和先天性畸形的原因不仅限于 NAD 合成途径基因的罕见双等位基因突变。相反，单等位基因遗传变异和环境因素可能导致类似的结果。这些结果扩展了我们对先天性畸形原因的理解，以及在怀孕期间充分消耗 NAD 前体的重要性。
