OTC – Ornithine Transcarbamylase Deficiency

Ornithine transcarbamylase (OTC) deficiency is a well‐characterized X-linked recessive urea cycle disorder caused by loss-of-function variants in the OTC gene (HGNC:8512) leading to hyperammonemia and orotic aciduria in affected individuals, and is catalogued as Ornithine Transcarbamylase Deficiency (MONDO:0010703).

Inheritance is X-linked recessive, with hemizygous males typically presenting in the neonatal period, although heterozygous females may manifest later with variable expressivity due to skewed X-inactivation. Segregation in large pedigrees demonstrates clustering of affected males across generations, including one five-generation family with eight sudden male deaths in childhood or adolescence ([PMID:9007316]).

Genetic evidence for OTC deficiency is strong, with over 157 families reported bearing point mutations, deletions, splice-site and structural variants encompassing all ten exons of OTC, including recurrent CpG site transitions and de novo changes ([PMID:10946359]). The variant spectrum includes missense alleles such as c.985A>G (p.Asn329Asp), which was first identified in a hyperammonemic female presenting with orotic aciduria ([PMID:1456259]).

Functional assays confirm a loss-of-function mechanism: recombinant expression of missense mutants (e.g., R40H, R277W) in bacterial and mammalian cells reveals reduced enzyme activity, altered substrate affinity and protein instability ([PMID:9175746], [PMID:9609999]). The spf/ash mouse model carrying the human R129H splice-site mutation replicates partial exon skipping and hyperammonemia, and targeted U1snRNA rescue restores correct splicing and OTC expression in hepatocytes ([PMID:25853564], [PMID:33228018]).

No substantial conflicting evidence has emerged to dispute the OTC–OTCD association. The concordance of genetic, biochemical and animal model data establishes OTC deficiency as a definitive gene–disease relationship under ClinGen criteria.

Key Take-home: Genetic testing of OTC, with attention to coding and regulatory regions, is critical for diagnosis, family counseling and early intervention to prevent catastrophic hyperammonemic crises.

References

• American journal of diseases of children • 1992 • An unusual presentation of medium‐chain acyl coenzyme A dehydrogenase deficiency. PMID:1456259
• Clinical genetics • 1996 • Asymptomatic and late‐onset ornithine transcarbamylase (OTC) deficiency in males of a five‐generation family, caused by an A208T mutation. PMID:9007316
• American journal of medical genetics • 2000 • Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. PMID:10946359
• PLoS one • 2015 • Functional characterization of the spf/ash splicing variation in OTC deficiency of mice and man. PMID:25853564
• International journal of molecular sciences • 2020 • An Exon‐Specific Small Nuclear U1 RNA (ExSpeU1) Improves Hepatic OTC Expression in a Splicing‐Defective spf/ash Mouse Model of Ornithine Transcarbamylase Deficiency. PMID:33228018

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