Szot, Justin O. and Campagnolo, Carla and Cao, Ye and Iyer, Kavitha R. and Cuny, Hartmut and Drysdale, Thomas and Flores-Daboub, Josue A. and Bi, Weimin and Westerfield, Lauren and Liu, Pengfei and Leung, Tse Ngong and Choy, Kwong Wai and Chapman, Gavin and Xiao, Rui and Siu, Victoria M. and Dunwoodie, Sally L. (2020) Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders. The American Journal of Human Genetics, 106 (1). pp.129-136. ISSN 00029297
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Szot et al. 2020 AJHG Biallelic mutation in NADSYN1... (manuscript).pdf - Accepted Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (1MB) | Preview |
Abstract
Birth defects occur in up to 3% of all live births and are the leading cause of infant death. Here we present five individuals from four unrelated families, individuals who share similar phenotypes with disease-causal bi-allelic variants in NADSYN1, encoding NAD synthetase 1, the final enzyme of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway. Defects range from the isolated absence of both kidneys to multiple malformations of the vertebrae, heart, limbs, and kidney, and no affected individual survived for more than three months postnatally. NAD is an essential coenzyme for numerous cellular processes. Bi-allelic loss-of-function mutations in genes required for the de novo synthesis of NAD were previously identified in individuals with multiple congenital abnormalities affecting the heart, kidney, vertebrae, and limbs. Functional assessments of NADSYN1 missense variants, through a combination of yeast complementation and enzymatic assays, show impaired enzymatic activity and severely reduced NAD levels. Thus, NADSYN1 represents an additional gene required for NAD synthesis during embryogenesis, and NADSYN1 has bi-allelic missense variants that cause NAD deficiency-dependent malformations. Our findings expand the genotypic spectrum of congenital NAD deficiency disorders and further implicate mutation of additional genes involved in de novo NAD synthesis as potential causes of complex birth defects.
| Item Type: | Article |
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| Subjects: | R Medicine > R Medicine (General) |
| Divisions: | Faculty of Medicine, Health and Life Sciences > School of Medicine |
| Depositing User: | Repository Administrator |
| Date Deposited: | 23 Jan 2020 04:21 |
| Last Modified: | 12 Mar 2021 02:48 |
| URI: | http://eprints.victorchang.edu.au/id/eprint/917 |
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