OTC variants cause OTC deficiency

The gene encoding OTC has 10 exons and produces a 354‑amino‑acid precursor, processed to a 322‑amino‑acid mature enzyme organized as a homotrimer containing three active sites. An N-terminal leader sequence (~34 aa) is required for mitochondrial targeting. Several motifs have been identified in OTC that contribute to ornithine and carbamoyl phosphate binding and catalysis; there is additionally an SMG motif (serine 267, methionine 268 and glycine 269) that is thought to undergo conformational changes upon substrate binding to cap the active site (Shi et al, 1998; Shi et al, 2000; Shi et al, 2001; reviewed in Couchet et al, 2021).

Mutations in the OTC gene give rise to OTC deficiency (OTCD; OMIM 311250), the most common of the urea cycle disorders (reviewed in Couchet et al, 2021; Schmitt Ribas et al, 2022). OTC deficiency may present neonatally or later in development depending on the severity of the underlying mutation, and like most disorders of the urea cycle, is characterized by hyperammonemia with resulting neurological consequences (reviewed in Schmitt Ribas et al, 2022; Couchet et al, 2021).