New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder.
Por:
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 E, Dupuis L, James Stavropoulos D, McNiven V, Mendoza-Londono R, Elliott AM, Phillips RS, Chapman G and Dunwoodie SL
Publicada:
1 jul 2021
Ahead of Print:
16 may 2021
Resumen:
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.
Filiaciones:
Szot JO:
Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
Slavotinek A:
Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
Chong K:
Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada
Brandau O:
SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany
Nezarati M:
Genetics Program, North York General Hospital, Toronto, Ontario, Canada
Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
Cueto-González AM:
Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Patel MS:
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
Devine WP:
Department of Anatomic Pathology, University of California, San Francisco, California, USA
Rego S:
Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
Acyinena AP:
Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
Shannon P:
Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
Myles-Reid D:
Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada
Blaser S:
The Hospital for Sick Children, Toronto, Ontario, Canada
Mieghem TV:
Fetal Medicine Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada
Yavuz-Kienle H:
SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany
Skladny H:
SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany
Miller K:
Genetics Program, North York General Hospital, Toronto, Ontario, Canada
Riera MDT:
Metabolic Unit and Pediatric Neurology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Martínez SA:
Fetal Medicine Unit and Obstetrics Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Tizzano E:
Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Medicine Genetics Group, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, Autonomous University of Barcelona, Barcelona, Spain
Dupuis L:
Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
James Stavropoulos D:
Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
McNiven V:
Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Mendoza-Londono R:
Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Elliott AM:
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
CAUSES Study:
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
Phillips RS:
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, USA
Department of Chemistry, University of Georgia, Athens, Georgia, USA
Chapman G:
Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
Dunwoodie SL:
Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
Green Accepted
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