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Szot JO, Slavotinek A, Chong K, et al. New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder. Hum Mutat. 2021;42(7):862-876doi: 10.1002/humu.24211.
Szot, J. O., Slavotinek, A., Chong, K., Brandau, O., Nezarati, M., Cueto-González, A. M., Patel, M. S., Devine, W. P., Rego, S., Acyinena, A. P., Shannon, P., Myles-Reid, D., Blaser, S., Mieghem, T. V., Yavuz-Kienle, H., Skladny, H., Miller, K., Riera, M. D. T., Martínez, S. A., Tizzano, E. F., Dupuis, L., James Stavropoulos, D., McNiven, V., Mendoza-Londono, R., Elliott, A. M., Phillips, R. S., Chapman, G., & Dunwoodie, S. L. (2021). New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder. Human mutation, 42(7), 862-876. https://doi.org/10.1002/humu.24211
Szot, Justin O, et al. "New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder." Human mutation vol. 42,7 (2021): 862-876. doi: https://doi.org/10.1002/humu.24211
Szot JO, Slavotinek A, Chong K, Brandau O, Nezarati M, Cueto-González AM, Patel MS, Devine WP, Rego S, Acyinena AP, Shannon P, Myles-Reid D, Blaser S, Mieghem TV, Yavuz-Kienle H, Skladny H, Miller K, Riera MDT, Martínez SA, Tizzano EF, Dupuis L, James Stavropoulos D, McNiven V, Mendoza-Londono R, Elliott AM, Phillips RS, Chapman G, Dunwoodie SL. New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder. Hum Mutat. 2021 Jul;42(7):862-876. doi: 10.1002/humu.24211. Epub 2021 May 16. PMID: 33942433; PMCID: PMC8238843.
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Hum Mutat. 2021 Jul;42(7):862-876. doi: 10.1002/humu.24211. Epub 2021 May 16.

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

Human mutation

Justin O Szot, Anne Slavotinek, Karen Chong, Oliver Brandau, Marjan Nezarati, Anna M Cueto-González, Millan S Patel, Walter P Devine, Shannon Rego, Alicia P Acyinena, Patrick Shannon, Diane Myles-Reid, Susan Blaser, Tim V Mieghem, Halenur Yavuz-Kienle, Heyko Skladny, Kristen Miller, Miereia D T Riera, Silvia A Martínez, Eduardo F Tizzano, Lucie Dupuis, Dimitri James Stavropoulos, Vanda McNiven, Roberto Mendoza-Londono, Alison M Elliott, Robert S Phillips, Gavin Chapman, Sally L Dunwoodie

Affiliations

  1. Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
  2. Department of Pediatrics, University of California San Francisco, San Francisco, California, USA.
  3. Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada.
  4. SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany.
  5. Genetics Program, North York General Hospital, Toronto, Ontario, Canada.
  6. Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
  7. Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  8. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
  9. Department of Anatomic Pathology, University of California, San Francisco, California, USA.
  10. Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
  11. The Hospital for Sick Children, Toronto, Ontario, Canada.
  12. Fetal Medicine Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada.
  13. Metabolic Unit and Pediatric Neurology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  14. Fetal Medicine Unit and Obstetrics Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  15. Medicine Genetics Group, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, Autonomous University of Barcelona, Barcelona, Spain.
  16. Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  17. Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
  18. Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, USA.
  19. Department of Chemistry, University of Georgia, Athens, Georgia, USA.
  20. Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
  21. Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia.

PMID: 33942433 PMCID: PMC8238843 DOI: 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.

© 2021 Wiley Periodicals LLC.

Keywords: HAAO ; KYNU ; de novo NAD biosynthesis; Congenital NAD Deficiency Disorder; NAD; kynurenine pathway; nicotinamide adenine dinucleotide

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