A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.
СтатьяПоддержка службы здравоохранения СШАПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Szot Justin O, Cuny Hartmut, Martin Ella Mma, Sheng Delicia Z, Iyer Kavitha, Portelli Stephanie, Nguyen Vivien, Gereis Jessica M, Alankarage Dimuthu, Chitayat David, Chong Karen, Wentzensen Ingrid M, Vincent-Delormé Catherine, Lermine Alban, Burkitt-Wright Emma, Ji Weizhen, Jeffries Lauren, Pais Lynn S, Tan Tiong Y, Pitt James, Wise Cheryl A, Wright Helen, Andrews Israel D, Pruniski Brianna, Grebe Theresa A, Corsten-Janssen Nicole, Bouman Katelijne, Poulton Cathryn, Prakash Supraja, Keren Boris, Brown Natasha J, Hunter Matthew F, Heath Oliver, Lakhani Saquib A, McDermott John H, Ascher David B, Chapman Gavin, Bozon Kayleigh, Dunwoodie Sally L
Аннотация
Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.