{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNADSYN1 encodes nicotinamide adenine dinucleotide (NAD) synthetase 1, an enzyme that has been implicated in vitamin D metabolism. Genome‐wide association studies have identified polymorphisms at the DHCR7/NADSYN1 locus that correlate with circulating levels of 25‑hydroxy‐vitamin D, thereby influencing a range of conditions—from rickets and osteoporosis to cardiovascular and neurodegenerative diseases. In addition, variants in this locus have been linked to differences in height and autoimmune disorders such as rheumatoid arthritis, underscoring a broader impact on metabolic and inflammatory pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the biochemical level, NADSYN1 functions as the final enzyme in the de novo synthesis pathway of NAD⁺, a vital coenzyme for a myriad of cellular metabolic processes. Structural and functional analyses of the human enzyme reveal distinct substrate specificities—differing from those of bacterial counterparts—which highlight its essential role in regulating and maintaining intracellular NAD levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, biallelic loss-of-function mutations in NADSYN1 have been linked to congenital NAD deficiency disorders, including conditions such as Vertebral-Cardiac-Renal-Limb (VCRL) syndrome. Affected individuals exhibit a spectrum of multi-organ malformations—ranging from isolated renal anomalies to complex defects involving the heart, vertebrae, and limbs—with many cases resulting in perinatal lethality or severe developmental delay. Functional studies demonstrate that these pathogenic variants disrupt enzymatic activity, markedly reducing NAD levels and therefore impairing critical processes during embryogenesis. The expanding genotypic spectrum of NADSYN1-associated disorders further implicates its central role in organ development and metabolic homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jiyoung Ahn, Kai Yu, Rachael Stolzenberg-Solomon, et al. 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