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New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder
- Source :
- Human mutation, 42(7), 862-876. Wiley-Liss Inc., Hum Mutat
- Publication Year :
- 2021
- Publisher :
- Hindawi Limited, 2021.
-
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.
- 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
Subjects
Details
- ISSN :
- 10981004 and 10597794
- Volume :
- 42
- Database :
- OpenAIRE
- Journal :
- Human Mutation
- Accession number :
- edsair.doi.dedup.....4cb52f60e935bbd489940ccdd80426e3