A promoter variant in theOTCgene associated with late and variable age of onset hyperammonemia

Abstract

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.

Intronic variants in inborn errors of metabolism: Beyond the exome

“…Sequencing of the promoter region identified a c.-106C>A variant, which had been reported previously in three other males with late-onset disease ( Jang et al, 2018 ). A dual luciferase assay demonstrated that this promoter variant resulted in 10% of normal gene expression ( Han et al, 2022 ). This was consistent with the milder clinical features of affected males.…”

Father-to-daughter transmission in late-onset OTC deficiency: an underestimated mechanism of inheritance of an X-linked disease

“…Among urea cycle defects, OTCD is the only inherited as an X-linked recessive trait. Hemizygous males are usually affected by a very severe neonatal-onset form or, less frequently, by a late-onset form, with milder disease course, mainly depending on the OTC residual enzymatic activity [ 6 , 7 ]. Symptoms of this late-onset form include recurrent vomiting, protein aversion, unexplained hepatopathy, intermittent neurological and psychiatric symptoms with emotional or personality changes, up to an overt encephalopathy with seizures and coma.…”

Father-to-daughter transmission in late-onset OTC deficiency: an underestimated mechanism of inheritance of an X-linked disease

“…Patients may remain asymptomatic even for long periods of time, or may present chronic disease course with intermittent episodes of hyperammonemia which are often triggered by intercurrent illnesses, dietary changes, drugs exposure (e.g. valproate, asparaginase), catabolic stressors or prolonged fasting [7][8][9][10][11].…”

“…Among urea cycle defects, OTCD is the only inherited as an X-linked recessive trait. Hemizygous males are usually affected by a very severe neonatal-onset form or, less frequently, by a late-onset form, with milder disease course, mainly depending on the OTC residual enzymatic activity [6,7]. Symptoms of this late-onset form include recurrent vomiting, protein aversion, unexplained hepatopathy, intermittent neurological and psychiatric symptoms with emotional or personality changes, up to an overt encephalopathy with seizures and coma.…”