Mutations that disrupt de novo synthesis of nicotinamide adenine dinucleotide (NAD) were associated with multiple congenital malformations in humans and mice, and supplementing niacin during gestation prevented these malformations in mice, new research suggests.
The malformations include vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL), “a nonrandom combination of congenital defects without a known cause,” wrote Hongjun Shi, PhD, of Victor Chang Cardiac Research Institute, New South Wales, Australia, and colleagues (N Engl J Med. 2017;377:544-52).
Numerous genetic and environmental factors can potentially cause NAD deficiency during gestation and the investigators suggested collectively referring to the resulting malformations as “congenital NAD deficiency disorders.”
Congenital defects can occur together in newborns more often than would be expected by chance, but “in many such cases, it has proved difficult to identify a genetic cause,” the investigators noted. Using genomic sequencing, they looked for possible pathogenic gene variants within four unrelated families in which a person was born with multiple congenital malformations. Next, they evaluated the function of the variants by testing in vitro enzyme activity and measuring relevant plasma metabolites. Finally, they used the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 system to create mouse models with similar variants.
This approach identified variants in two genes encoding enzymes of the kynurenine pathway: 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients had homozygous variants associated with loss-of-function changes in these proteins. A fourth patient had heterozygous variants in the gene encoding KYNU.
“The mutant enzymes had greatly reduced activity in vitro,” the researchers wrote. Patients had decreased circulating levels of NAD, which tryptophan synthesizes through the kynurenine pathway. Notably, mouse embryos lacking the mouse equivalents of HAAO or KYNU also had congenital defects associated with NAD deficiency. Preventing NAD deficiency during gestation averted these defects in mice.
“The NAD de novo synthesis pathway catabolizes tryptophan,” the researchers added. “Although metabolite levels upstream of the block are elevated, and the metabolites have postnatal functions, we found that it is the deficiency in embryonic NAD, downstream of the block, that is disrupting embryogenesis.”
The study was supported by the Australian and New South Wales governments and foundations. The investigators reported having no other financial disclosures.