@article{67d9a39538c94eda97e6ac1eae17988d,
title = "NAD deficiency, congenital malformations, and niacin supplementation",
abstract = "BACKGROUND: Congenital malformations can be manifested as combinations of phenotypes that co-occur 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.",
author = "Hongjun Shi and Annabelle Enriquez and Melissa Rapadas and Martin, {Ella M.M.A.} and Roni Wang and Julie Moreau and Lim, {Chai K.} and Szot, {Justin O.} and Eddie Ip and Hughes, {James N.} and Kotaro Sugimoto and Humphreys, {David T.} and McInerney-Leo, {Aideen M.} and Leo, {Paul J.} and Maghzal, {Ghassan J.} and Jake Halliday and Janine Smith and Alison Colley and Mark, {Paul R.} and Felicity Collins and Sillence, {David O.} and Winlaw, {David S.} and Ho, {Joshua W.K.} and Guillemin, {Gilles J.} and Brown, {Matthew A.} and Kazu Kikuchi and Thomas, {Paul Q.} and Roland Stocker and Eleni Giannoulatou and Gavin Chapman and Duncan, {Emma L.} and Sparrow, {Duncan B.} and Dunwoodie, {Sally L.}",
note = "Funding Information: (Funded by the National Health and Medical Research Council of Australia and others.) Supported by fellowships (ID514900; ID1042002, to Dr. Dunwoodie; ID1111632, to Dr. Stocker; and ID1105271, to Dr. Ho), project grants (ID635500, to Drs. Dunwoodie and Sparrow; ID1044543, to Drs. Dunwoodie, Duncan, and Sparrow; ID1102373, to Drs. Dunwoodie, Ho, Kikuchi, and Thomas; and ID1130247, to Dr. Kikuchi), and program grants (ID1074386, to Dr. Dunwoodie; and ID 1052616, to Dr. Stocker) from the National Health and Medical Research Council of Australia; a grant (ID1052616, to Dr. Stocker) and a fellowship (FT110100836, to Dr. Kikuchi) from the Australian Research Council; fellowships (ID100848, to Dr. Ho; and ID101204, to Dr. Giannoulatou) from the Australian National Heart Foundation; a Queensland Premier{\textquoteright}s Fellowship (to Dr. Brown); and grants from the Kirby Foundation (to Dr. Ho), the New South Wales Government Office for Health and Medical Research (to Drs. Dunwoodie and Stocker), the Chain Reaction Challenge Foundation (to Drs. Dunwoodie and Winlaw), and the Key Foundation (to Drs. Dunwoodie and Winlaw). We thank the patients and families for their participation and cooperation, the staff of the Exome Aggregation Consortium, and the groups that provided exome variant data for comparison. A full list of contributing groups is available at http://exac.broadinstitute.org/about.",
year = "2017",
month = aug,
day = "10",
doi = "10.1056/NEJMoa1616361",
language = "English",
volume = "377",
pages = "544--552",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "6",
}