Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene

Abstract

Ornithine transcarbamylase (OTC) deficiency is the most common inherited disorder of the urea cycle and is transmitted as an X-linked trait. Defects in the OTC gene cause a block in ureagenesis resulting in hyperammonemia, which can lead to brain damage and death. Three previous mutation updates for the OTC gene have been published, in 1993, 1995, and 2002. The most recent comprehensive update, in 2002, contained 244 mutations including 13 nondisease-causing mutations and polymorphisms. This current update reports 341 mutations, of which 93 have not been previously reported, and an additional 29 nondisease-causing mutations and polymorphisms. Out of the 341 mutations, 149 were associated with neonatal onset of hyperammonemia (within the first week of life), 70 were seen in male patients with later onset of hyperammonemia, and 121 were found in heterozygous females (one unknown). Along with the reported mutations, residual enzyme activities and other pertinent clinical information are included whenever available. Most mutations in the OTC gene are specific to a particular family ("private" mutations). They are distributed throughout the gene, with a significant paucity of mutations in the 32 first codons encoding the "leader" peptide (exon 1 and the beginning of exon 2). Almost all mutations in consensus splice sites confer a neonatal onset phenotype. Using the current molecular screening methods, mutations are found in about 80% of the patients. The remaining patients may have mutations in regulatory domains or mutations deep in the introns, which constitute 98.5% of the genomic sequence. In addition, a phenocopy of OTC deficiency caused by mutations in another unknown gene cannot be excluded.

Complex management of a patient with a contiguous Xp11.4 gene deletion involving ornithine transcarbamylase: A role for detailed molecular analysis in complex presentations of classical diseases

“…These cases are wellknown and were instrumental in identifying the NR0B1 (DAX1), GK, DMD, CYBB, and RPGR genes ( Figure 1, Table 1; and references therein). In addition, a number of cases resulted in neonatal lethal OTCD caused by deletions of OTC, but minimal further analysis was performed [2][3][4]34,35] . Upon review of the literature, the two cases reported here appear to be the only males reported with a deletion of Xp11.4-Xp21.2 centromeric of DMD and including OTC.…”

“…Most mutations are 'private' single nucleotide substitutions or small insertions or deletions [2][3][4]. OTCD perturbs urea cycle function and results in variable degrees of hyperammonemia depending on the extent of enzyme deficiency.…”

Stable isotopes in the diagnosis and treatment of inherited hyperammonemia

“…However, pathological mutations are not always identified [23,24] and even when they are found, they may not provide much prognostic information, especially in the case of heterozygotes of OTC deficiency, the most common urea cycle disorder [25]. This may result in some scenarios where the non-invasive determination of urea cycle function can greatly contribute to clinical management.…”

Ornithine transcarbamylase (OTC) deficiency based on a hemizygous p.R277W mutation causing life-threatening hyperammonemic crisis during treatment for Hodgkin’s lymphoma

“…Currently, more than 300 mutations compromising enzyme activity are known [1]. OTC deficiency is an X-linked disorder [2] that represents the most frequent inherited urea cycle defect.…”