Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder
Justin O. Szot, … , Kayleigh Bozon, Sally L. Dunwoodie
Justin O. Szot, … , Kayleigh Bozon, Sally L. Dunwoodie
Published February 15, 2024
Citation Information: J Clin Invest. 2024;134(4):e174824. https://doi.org/10.1172/JCI174824.
View: Text | PDF
Research Article Reproductive biology

A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder

  • Text
  • PDF
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.

Authors

Justin O. Szot, Hartmut Cuny, Ella M.M.A. Martin, Delicia Z. Sheng, Kavitha Iyer, Stephanie Portelli, Vivien Nguyen, Jessica M. Gereis, Dimuthu Alankarage, David Chitayat, Karen Chong, Ingrid M. Wentzensen, Catherine Vincent-Delormé, Alban Lermine, Emma Burkitt-Wright, Weizhen Ji, Lauren Jeffries, Lynn S. Pais, Tiong Y. Tan, James Pitt, Cheryl A. Wise, Helen Wright, Israel D. Andrews, Brianna Pruniski, Theresa A. Grebe, Nicole Corsten-Janssen, Katelijne Bouman, Cathryn Poulton, Supraja Prakash, Boris Keren, Natasha J. Brown, Matthew F. Hunter, Oliver Heath, Saquib A. Lakhani, John H. McDermott, David B. Ascher, Gavin Chapman, Kayleigh Bozon, Sally L. Dunwoodie

×

Graphical abstract

Options: View larger image (or click on image)

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts