Diversity Supplement: BCM Center for Precision Medicine Models

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ABSTRACT Recent studies have reported that genetic disruptions of the kynurenine pathway (KP) are a cause of congenital nicotinamide adenine dinucleotide (NAD) deficiencies in families with a history of birth defects and recurrent miscarriages. Mammals synthesize NAD+ from two different pathways. The KP biosynthesizes NAD+ de novo from dietary tryptophan, whereas the Preiss-Handler pathway utilizes dietary niacin. Birth defects associated with KP disruptions include phenotypes of vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies; some patients have developmental delay, learning disorders, autism, and/or microcephaly. Through the Undiagnosed Diseases Network site at Baylor College of Medicine (BCM), we have identified a patient with biallelic variants in the kynurenine 3-monooxygenase (KMO) gene, which encodes a key enzyme in the KP. The patient has congenital anomalies, short stature, and neurocognitive delays, representing a novel congenital NAD deficiency disorder (CNDD). In addition, she has extreme elevations in the serum levels of upstream metabolites (kynurenine and kynurenate). Dysregulation of these same metabolites have previously been linked to neuropsychiatric phenotypes in human patients with no obvious inborn errors of metabolism. Therefore, we hypothesize that KMO deficiency, a novel congenital NAD deficiency disorder, increases the risk for congenital anomalies and postnatal phenotypes, some of which are preventable with niacin supplementation. The Baylor College of Medicine (BCM) Center for Precision Medicine Models generates precision mouse models to support the discovery of novel undiagnosed disorders like KMO deficiency. These models serve as resources for additional pre-clinical studies investigating personalized and preventative medicine approaches to their care. Within the parent grant, we generated Kmo knockout (Kmo-/-) mice to explore the increased vulnerability of Kmo-/- embryos to congenital anomalies in the setting of low niacin diet. We will extend the studies in the parent grant to further characterize the prenatal and postnatal phenotypes associated with KMO deficiency and test whether niacin supplementation prevents the phenotypes. Thus, my proposed studies will demonstrate that biallelic loss-of-function variants in KMO cause a novel form of CNDD and demonstrate whether niacin supplementation prenatally or postnatally may prevent phenotypes associated with this new disorder. These findings will have the potential to benefit individuals with CNDD as well as provide insights into the role of NAD and kynurenine metabolism in normal prenatal and postnatal development.