New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder

Szot, Justin O. and Slavotinek, Anne and Chong, Karen and Brandau, Oliver and Nezarati, Marjan and Cueto‐González, Anna M. and Patel, Millan S. and Devine, Walter P. and Rego, Shannon and Acyinena, Alicia P. and Shannon, Patrick and Myles‐Reid, Diane and Blaser, Susan and Mieghem, Tim V. and Yavuz‐Kienle, Halenur and Skladny, Heyko and Miller, Kristen and Riera, Miereia D. T. and Martínez, Silvia A. and Tizzano, Eduardo F. and Dupuis, Lucie and James Stavropoulos, Dimitri and McNiven, Vanda and Mendoza‐Londono, Roberto and Elliott, Alison M. and Phillips, Robert S. and Chapman, Gavin and Dunwoodie, Sally L. (2021) New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder. Human Mutation, 42 (7). pp.862-876. ISSN 1059-7794

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Link to published document: http://doi.org/10.1002/humu.24211

Abstract

Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme 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 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 a 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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 31 Jul 2021 05:46
Last Modified: 31 Jul 2021 05:46
URI: http://eprints.victorchang.edu.au/id/eprint/1102

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