NAD deficiency, congenital malformations, and niacin supplementation

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dc.contributor.authorShi, H.
dc.contributor.authorEnriquez, A.
dc.contributor.authorRapadas, M.
dc.contributor.authorMartin, E.
dc.contributor.authorWang, R.
dc.contributor.authorMoreau, J.
dc.contributor.authorLim, C.
dc.contributor.authorSzot, J.
dc.contributor.authorIp, E.
dc.contributor.authorHughes, J.
dc.contributor.authorSugimoto, K.
dc.contributor.authorHumphreys, D.
dc.contributor.authorMcInerney-Leo, A.
dc.contributor.authorLeo, P.
dc.contributor.authorMaghzal, G.
dc.contributor.authorHalliday, J.
dc.contributor.authorSmith, J.
dc.contributor.authorColley, A.
dc.contributor.authorMark, P.
dc.contributor.authorCollins, F.
dc.contributor.authoret al.
dc.date.issued2017
dc.descriptionAugust 10, 2017
dc.description.abstractBACKGROUND 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.)
dc.description.statementofresponsibilityHongjun Shi ... James N. Hughes ... Paul Q. Thomas ... et al.
dc.identifier.citationNew England Journal of Medicine, 2017; 377(6):544-552
dc.identifier.doi10.1056/nejmoa1616361
dc.identifier.issn0028-4793
dc.identifier.issn1533-4406
dc.identifier.urihttp://hdl.handle.net/2440/107491
dc.language.isoen
dc.publisherMassachusetts Medical Society
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/514900
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1042002
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1111632
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1105271
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/635500
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1044543
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1102373
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1130247
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1074386
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1052616
dc.relation.granthttp://purl.org/au-research/grants/arc/FT110100836
dc.rightsCopyright © 2017 Massachusetts Medical Society. All rights reserved.
dc.source.urihttps://doi.org/10.1056/nejmoa1616361
dc.subjectSpine
dc.subjectEsophagus
dc.subjectTrachea
dc.subjectKidney
dc.subjectAnimals
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjectLimb Deformities, Congenital
dc.subjectHeart Defects, Congenital
dc.subjectDisease Models, Animal
dc.subjectNiacin
dc.subjectNAD
dc.subjectHydrolases
dc.subjectSequence Analysis, DNA
dc.subjectMutation
dc.subjectDietary Supplements
dc.subjectAnal Canal
dc.subjectFemale
dc.subjectMale
dc.subject3-Hydroxyanthranilate 3,4-Dioxygenase
dc.subjectCongenital Abnormalities
dc.titleNAD deficiency, congenital malformations, and niacin supplementation
dc.typeJournal article
pubs.publication-statusPublished

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