Mutations and polymorphisms in the human ornithine transcarbamylase gene

Abstract

Ornithine transcarbamylase (OTC) deficiency, an X-linked, semidominant disorder, is the most common inherited defect in ureagenesis resulting in hyperammonemia. The previous two mutation updates for the OTC gene were published in 1993 and 1995 and included 36 and 30 mutations respectively. This comprehensive update contains a compilation of 244 mutations including 13 polymorphisms. Twenty-four of the mutations are reported here for the first time. Forty-two percent of the disease-causing mutations are associated with acute neonatal hyperammonemia; 21% were found in patients with late onset disease and approximately 37% were found in manifesting heterozygous females, most of which are presumed to confer a neonatal phenotype in hemizygous males. Also included are residual enzyme activities and residual incorporation of ammonium nitrogen into urea and results of expression studies for a small proportion of the mutations. Most mutations in the OTC gene are "private" and are distributed throughout the gene with paucity of mutation in the sequence encoding the leader peptide (exon 1 and beginning of exon 2) and in exon 7. Almost all mutations in consensus splicing sites confer a neonatal phenotype. Thirteen polymorphisms have been found, several of which are useful for allele tracking in patients in whom the mutation can't be found. Even with sequencing of the entire reading frame and exon/intron boundaries, only about 80% of the mutations are detected in patients with proven OTC deficiency. The remaining probably occur within the introns or in regulatory domains.

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.…”

In vivo assessment of mutations in OTC for dominant-negative effects following rAAV2/8-mediated gene delivery to the mouse liver

“…1 Mutations in the OTC gene range from deletions and insertions to point mutations that affect either protein activity and/or stability. 2 Undetectable enzyme activity causes severe neonatal hyperammonemia and is associated with a high risk of coma and death, and significant morbidity in those surviving the newborn period. Patients with as little as 3% normal enzyme activity have a mild or late presenting phenotype more readily managed with contemporary therapy.…”

“…Patients with as little as 3% normal enzyme activity have a mild or late presenting phenotype more readily managed with contemporary therapy. 2 Thus, for patients with the severe neonatal form, even relatively low levels of gene correction are likely to confer significant therapeutic benefit. One possible limitation of gene therapy in this setting, however, is the patient's mutant enzyme exerting a dominant-negative effect on vector-encoded wild-type OTC.…”

Potential of AAV vectors in the treatment of metabolic disease

“…Patients with as little as 3% residual enzyme activity have a milder phenotype more readily managed by conventional therapy. 66,67 Two mouse models of OTC deficiency exist, spf and spf ash mice, each with less than 10% wild-type enzyme activity. While not hyperammonemic these mice have excessive levels of orotic acid in their urine, a surrogate marker of OTC deficiency that allows longitudinal analysis of disease correction in individual mice.…”