Diversity Supplement: BCM Center for Precision Medicine Models

摘要 最近的研究报道，犬尿氨酸途径(KP)的遗传中断是导致 有出生缺陷史和家族史的先天性烟酰胺腺嘌呤二核苷酸缺乏症 反复流产。哺乳动物通过两种不同的途径合成NAD+。KP生物合成NAD+ 从饮食色氨酸开始，而Preiss-Handler途径利用饮食烟酸。出生缺陷 与KP中断相关的表型包括脊椎、肛门、心脏、气管食道、肾脏和 肢体畸形；一些患者有发育迟缓、学习障碍、自闭症和/或小头畸形。 通过贝勒医学院(BCM)的未诊断疾病网络站点，我们已经确定了一个 患有犬尿氨酸3-单加氧酶(KMO)基因双等位变异的患者，该基因编码一种关键酶 在金伯利进程。患者有先天性畸形、身材矮小和神经认知迟缓，这是一种新的 先天性NAD缺乏障碍(CNDD)。此外，她的血清水平也出现了极端升高 上游代谢物(犬尿氨酸和犬尿酸)。这些相同代谢物的失调之前 与没有明显先天代谢障碍的人类患者的神经精神表型有关。 因此，我们假设KMO缺乏症，一种新的先天性NAD缺乏症，增加 先天畸形和出生后表型的风险，其中一些是烟酸可以预防的 补充。贝勒医学院(BCM)精确医学模型中心生成 精确的小鼠模型支持发现新的未诊断的疾病，如KMO缺乏症。这些 模型可作为研究个性化和预防性的其他临床前研究的资源 医学接近他们的治疗方法。在父母的资助中，我们产生了KMO基因敲除(KMO-/-)小鼠 探讨低烟酸饮食环境下KMO-/-胚胎对先天异常的易感性增加。 我们将扩展父母资助的研究，以进一步确定出生前和出生后的表型。 与KMO缺乏症相关，并测试补充烟酸是否能阻止表型。因此，我的 拟议的研究将证明KMO中的双等位功能丧失变异导致一种新形式的CNDD 并证明了产前或产后补充烟酸是否可以防止相关的表型 这种新的紊乱状态。这些发现将有可能使CNDD患者以及 深入了解NAD和犬尿氨酸代谢在正常产前和出生后的作用 发展。

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.