@article{5733b14942de4544beaefea2f27d1f86,
title = "A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder",
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.",
author = "Szot, {Justin O.} and Hartmut Cuny and Martin, {Ella M.M.A.} and Sheng, {Delicia Z.} and Kavitha Iyer and Stephanie Portelli and Vivien Nguyen and Gereis, {Jessica M.} and Dimuthu Alankarage and David Chitayat and Karen Chong and Wentzensen, {Ingrid M.} and Catherine Vincent-Delorm{\'e} and Alban Lermine and Emma Burkitt-Wright and Weizhen Ji and Lauren Jeffries and Pais, {Lynn S.} and Tan, {Tiong Y.} and James Pitt and Wise, {Cheryl A.} and Helen Wright and Andrews, {Israel D.} and Brianna Pruniski and Grebe, {Theresa A.} and Nicole Corsten-Janssen and Katelijne Bouman and Cathryn Poulton and Supraja Prakash and Boris Keren and Brown, {Natasha J.} and Hunter, {Matthew F.} and Oliver Heath and Lakhani, {Saquib A.} and McDermott, {John H.} and Ascher, {David B.} and Gavin Chapman and Kayleigh Bozon and Dunwoodie, {Sally L.}",
note = "Funding Information: This research was supported by funds to SLD from the National Health and Medical Research Council (Principal Research Fellowship ID1135886, Leadership Level 3 Fellowship ID2007896, and Project Grant ID1162878); by a New South Wales Health Cardiovascular Research Capacity Program Senior Researcher Grant; and by philanthropic support from the Key Foundation. Concerning Family 6, sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, and National Heart, Lung, and Blood Institute grant UM1HG008900, and in part by National Human Genome Research Institute grant R01HG009141. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We acknowledge Joelene Greasby for her technical assistance, Monica Konstantino for patient enrollment, and Gregory Webster for his assistance with genetics assessment. We also acknowledge Robert Brink and David Zahra of the Mouse Engineering at Garvan/Australian BioResources (MEGA) service for their help in the design and generation of the Nadsyn1 CRISPR targeted allele. Finally, we thank the patients and their families for their participation in this study. Publisher Copyright: {\textcopyright} 2024, Szot et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",
year = "2024",
month = feb,
day = "15",
doi = "10.1172/JCI174824",
language = "English",
volume = "134",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",
}