Predoctoral Training Program in Human Genetics, McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Inherit Metab Dis. 2022 Jul;45(4):710-718. doi: 10.1002/jimd.12524. Epub 2022 Jun 28.
Ornithine transcarbamylase deficiency (OTCD) is an X-linked inborn error caused by loss of function variants in the OTC gene typically associated with severe neonatal hyperammonemia. Rare examples of late-onset OTCD have also been described. Here, we describe an OTC promoter variant, c.-106C>A, in a conserved HNF4a binding site, identified in two male siblings in Family 1 whose first and only recognized episodes of severe hyperammonemia occurred at ages 14 and 39 years, respectively. We identified the same OTC variant segregating in a large family with late-onset OTCD with variable expressivity (Family 2). We show that this OTC promoter variant reduces expression >5-fold in a dual-luciferase assay that tests promoter function. Addition of an upstream OTC enhancer increases expression of both the wild type and the c.-106C>A variant promoter constructs >5-fold with the mutant promoter still about fourfold lower than the wild type. Thus, in both contexts, the promoter variant results in substantially lower OTC expression. Under normal demand on urea cycle function, OTC expression in hemizygous males, although reduced, is sufficient to meet the demand for waste nitrogen excretion. However, in response to severe metabolic stress with attendant increased requirements on urea cycle function, the impaired promoter function results in inadequate OTC expression with resultant hyperammonemia. In the absence of precipitating events, hemizygotes with this allele are asymptomatic, explaining the late age of onset of hyperammonemia in affected individuals and the incomplete penetrance observed in some individuals in Family 2.
鸟氨酸氨甲酰基转移酶缺乏症（OTCD）是一种 X 连锁的先天性遗传缺陷，由 OTC 基因的功能丧失变异引起，通常与新生儿严重高氨血症有关。也有罕见的迟发性 OTCD 病例报道。在这里，我们描述了一个 OTC 启动子变异 c.-106C>A，位于一个保守的 HNF4a 结合位点，在 1 号家族的两名男性兄弟中发现，他们的首次且唯一被识别的严重高氨血症发作分别发生在 14 岁和 39 岁。我们在一个具有迟发性 OTCD 且表达性可变的大家族（2 号家族）中发现了同样的 OTC 变异。我们表明，该 OTC 启动子变异在双荧光素酶测定中使表达降低了>5 倍，该测定测试启动子功能。添加一个上游 OTC 增强子会使野生型和 c.-106C>A 变体启动子构建体的表达增加>5 倍，而突变体启动子的表达仍比野生型低约四倍。因此，在这两种情况下，启动子变异导致 OTC 表达显著降低。在尿素循环功能的正常需求下，虽然杂合子男性的 OTC 表达减少，但足以满足废物氮排泄的需求。然而，在严重的代谢应激伴随尿素循环功能需求增加的情况下，受损的启动子功能导致 OTC 表达不足，导致高氨血症。在没有诱发事件的情况下，携带该等位基因的杂合子无症状，这解释了受影响个体中高氨血症发病年龄较晚以及 2 号家族中一些个体观察到的不完全外显率的原因。
