ArticleThe Journal of clinical investigation2024
A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- Metabolic Reprogramming at the Maternal-Fetal Interface: Insights from Decidual Stromal Cells and Trophoblasts in Healthy Pregnancy Versus Recurrent Pregnancy Loss.International journal of molecular sciences · 2026Review
- Article
- The NAD-brain pharmacokinetic study of NAD augmentation in blood and brain using oral precursor supplementation.iScience · 2026Article
- Timing of NAD Deficiency During Organogenesis Dictates Defect Type and Penetrance.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Discovery and annotation of putative genes and novel RNA splice-isoforms in the human heart.Frontiers in cardiovascular medicine · 2026Article
- Identification of potential NAD-related biomarkers of recurrent miscarriage risk.Human reproduction (Oxford, England) · 2025Article
- Micronutrient Biomarker Selection and Assay Methods and Performance in Double-Blind, Randomized, Controlled Micronutrient Dose Response (MiNDR) Trials among Women of Reproductive Age and Pregnant Women in Rural Bangladesh.Current developments in nutrition · 2025Article
- Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Review
- Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects.eLife · 2025Article
- Pathobiochemistry of Aging and Neurodegeneration: Deregulation of NAD+ Metabolism in Brain Cells.Biomolecules · 2024Review
- The first century of JCI and beyond.The Journal of clinical investigation · 2024Article
- Regulation of and challenges in targeting NADNature reviews. Molecular cell biology · 2024Review
Corrections and comments
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Authors and funding
39 authors at 19 institutions in 6 countries.
Funding
Abstract
Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.
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