A zebrafish model of nicotinamide adenine dinucleotide (NAD) deficiency-derived congenital disorders.

Abstract

Developmental NADdeficiency is associated with diverse congenital malformations. Congenital NAD deficiency disorder (CNDD) is a multisystem developmental condition characterized by cardiac, renal, vertebral, and limb anomalies, among others. It is caused by biallelic pathogenic variants in genes involved in the nicotinamide adenine dinucleotide (NAD) synthesis pathway. CNDD anomalies overlap with clinical features described in vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL) association, suggesting a possible shared etiological link through NADdeficiency. However, the aberrant developmental mechanisms of NAD-deficient congenital anomalies remain poorly understood. To dynamically explore NAD-deficiency-induced congenital malformations, we developed a zebrafish model of NADdisruption. Zebrafish embryos treated with 2-amino-1,3,4-thiadiazole (ATDA), a known NADmetabolism disruptor, exhibited cardiac, tail, spinal cord, and craniofacial defects, which were partially rescued by nicotinamide (NAM) in a dose-dependent manner. Our work establishes zebrafish as a useful model for investigating how NADdeficiency contributes to multisystem congenital anomalies.