Please use this identifier to cite or link to this item: http://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.
RMID: 0030074198
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
Appears in Collections:Molecular and Biomedical Science publications

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