1. New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder
- Author
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Millan S. Patel, Halenur Yavuz-Kienle, Alicia P Acyinena, Diane Myles-Reid, Tim Van Mieghem, Anna M. Cueto-González, Causes Study, Susan Blaser, Miereia D T Riera, Silvia A Martínez, Shannon Rego, Walter Patrick Devine, Patrick Shannon, Karen Chong, Heyko Skladny, Sally L. Dunwoodie, Gavin Chapman, Justin O. Szot, Oliver Brandau, Dimitri J. Stavropoulos, Anne Slavotinek, Eduardo F. Tizzano, Alison M. Elliott, Vanda McNiven, Lucie Dupuis, Marjan M. Nezarati, Robert S. Phillips, Kristen Miller, Roberto Mendoza-Londono, ANS - Cellular & Molecular Mechanisms, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
- Subjects
Kynurenine pathway ,Genotype ,HAAO ,NADSYN1 ,Mutation, Missense ,de novo NAD biosynthesis ,KYNU ,Nicotinamide adenine dinucleotide ,Article ,Cofactor ,Frameshift mutation ,03 medical and health sciences ,chemistry.chemical_compound ,Genetics ,Animals ,Humans ,Missense mutation ,nicotinamide adenine dinucleotide ,Genetics (clinical) ,030304 developmental biology ,Mammals ,0303 health sciences ,biology ,030305 genetics & heredity ,NAD ,Spine ,Complementation ,Congenital NAD Deficiency Disorder ,chemistry ,biology.protein ,NAD+ kinase ,kynurenine pathway - Abstract
Nicotinamide adenine dinucleotide (NAD) is an essential cofactor involved in over 400 cellular reactions. During embryogenesis, mammals synthesize NAD de novo from dietary L-tryptophan via the kynurenine pathway. Biallelic, inactivating variants in three genes encoding enzymes of this biosynthesis pathway (KYNU, HAAO, and NADSYN1) disrupt NAD synthesis and have been identified in patients with multiple malformations of the heart, kidney, vertebrae, and limbs; these patients have Congenital NAD Deficiency Disorder. Here we have identified a further three families with biallelic variants in HAAO and four families with biallelic variants in KYNU. These patients present similarly with multiple malformations of the heart, kidney, vertebrae, and limbs, of variable severity. We show that each variant identified in these patients results in loss-of-function, revealed by significant reduction in NAD levels via yeast genetic complementation assays. For the first time missense mutations are identified as a cause of malformation and shown to disrupt enzyme function. These missense and frameshift variants cause moderate to severe NAD deficiency in yeast, analogous to insufficient synthesized NAD in patients. We hereby expand the genotypic and corresponding phenotypic spectrum of Congenital NAD Deficiency Disorder.
- Published
- 2021