Grant Abstract: Preventing KMO Deficiency-Associated Phenotypes with Niacin Supplementation

Grant Number: 3U54OD030165-04S2
PI Name: Heaney
Project Title: Preventing KMO Deficiency-Associated Phenotypes with Niacin Supplementation

Abstract: VACTERL (vertebral, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities) association is a constellation of congenital anomalies that affects roughly 1:10,000 births. Congenital nicotinamide adenine dinucleotide (NAD) deficiency, which is due to pathogenic variants in genes involved in NAD synthesis or recycling, has been identified recently as one cause for VACTERL-like phenotypes. We have identified two siblings with a history of congenital anomalies including cardiac, vertebral, kidney, and ear anomalies who share loss-of-function, biallelic variants in KMO, a gene which has not been previously associated with a Mendelian phenotype. KMO encodes an enzyme involved in NAD biosynthesis. KMO deficiency in the patients is associated with NAD deficiency and a striking increase in plasma kynurenine, the metabolite immediately upstream of the enzyme. Moreover, the surviving sibling has developed short stature and an apparent neurodevelopmental disorder. We hypothesize that KMO deficiency represents a novel form of congenital NAD deficiency that explains the congenital anomalies and postnatal phenotype in these siblings and that supplementation with niacin (also called nicotinic acid), an NAD precursor, may prevent the phenotypes associated with this deficiency. The Baylor College of Medicine (BCM) Center for Precision Medicine Models develops precision mouse models to end the diagnostic odyssey for patients like the siblings in our study. These models serve as resources for additional pre-clinical studies investigating personalized and preventative medicine approaches to their care. This application is in response to PA-20-227 from the Office of Dietary Supplements. Within the parent grant (U54OD030165), we generated Kmo-/- mice with the goal of demonstrating that loss of KMO causes congenital anomalies and that in utero niacin supplementation prevents these phenotypes. We aim to extend our studies to test whether niacin supplementation prevents the postnatal phenotypes associated with this disorder. In addition, we will investigate the metabolic mechanisms by which oral niacin supplementation impacts congenital NAD deficiency in KMO-deficient mice. Our studies, if successful, will demonstrate that KMO deficiency is a new cause for VACTERL-like phenotypes and will demonstrate which phenotypes may be preventable with prenatal and postnatal niacin supplementation. In addition, our proposed targeted metabolite studies and untargeted metabolomics studies will provide insights into which metabolic pathways are disrupted in this disorder and the impact of niacin supplementation on these pathways both in utero and in adulthood. Lastly, NAD deficiency has been linked to numerous common disorders including neurodegeneration, aging, mitochondrial myopathy, and retinopathy. Thus, the findings from our global metabolomics performed with and without niacin supplementation have the potential to have a broader impact beyond congenital NAD deficiency and embryonic development. PUBLIC HEALTH RELEVANCE: KMO deficiency is a new human disorder that causes low levels of nicotinamide adenine dinucleotide (NAD) and is associated with birth defects, poor growth, and developmental delays. Because NAD can be generated from niacin, we will test whether niacin will prevent the phenotypes associated with KMO deficiency. The results of this work have the potential to lend insights into the mechanisms underlying the association between low NAD levels and congenital anomalies and the impact of long-term niacin supplementation in KMO deficiency and other NAD deficiency disorders.

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