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https://hdl.handle.net/2440/107491
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Type: | Journal article |
Title: | NAD deficiency, congenital malformations, and niacin supplementation |
Author: | Shi, H. Enriquez, A. Rapadas, M. Martin, E. Wang, R. Moreau, J. Lim, C. Szot, J. Ip, E. Hughes, J. Sugimoto, K. Humphreys, D. McInerney-Leo, A. Leo, P. Maghzal, G. Halliday, J. Smith, J. Colley, A. Mark, P. Collins, F. et al. |
Citation: | New England Journal of Medicine, 2017; 377(6):544-552 |
Publisher: | Massachusetts Medical Society |
Issue Date: | 2017 |
ISSN: | 0028-4793 1533-4406 |
Statement of Responsibility: | Hongjun Shi ... James N. Hughes ... Paul Q. Thomas ... et al. |
Abstract: | BACKGROUND Congenital malformations can be manifested as combinations of phenotypes that cooccur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients. METHODS We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 system. RESULTS Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects. CONCLUSIONS Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice. (Funded by the National Health and Medical Research Council of Australia and others.) |
Keywords: | Spine Esophagus Trachea Kidney Animals Mice, Knockout Humans Mice Limb Deformities, Congenital Heart Defects, Congenital Disease Models, Animal Niacin NAD Hydrolases Sequence Analysis, DNA Mutation Dietary Supplements Anal Canal Female Male 3-Hydroxyanthranilate 3,4-Dioxygenase Congenital Abnormalities |
Description: | August 10, 2017 |
Rights: | Copyright © 2017 Massachusetts Medical Society. All rights reserved. |
DOI: | 10.1056/nejmoa1616361 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/514900 http://purl.org/au-research/grants/nhmrc/1042002 http://purl.org/au-research/grants/nhmrc/1111632 http://purl.org/au-research/grants/nhmrc/1105271 http://purl.org/au-research/grants/nhmrc/635500 http://purl.org/au-research/grants/nhmrc/1044543 http://purl.org/au-research/grants/nhmrc/1102373 http://purl.org/au-research/grants/nhmrc/1130247 http://purl.org/au-research/grants/nhmrc/1074386 http://purl.org/au-research/grants/nhmrc/1052616 http://purl.org/au-research/grants/arc/FT110100836 |
Published version: | http://dx.doi.org/10.1056/nejmoa1616361 |
Appears in Collections: | Aurora harvest 8 Molecular and Biomedical Science publications |
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