Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity.

Understanding the role of common polymorphisms in modulating the clinical phenotype when they co-occur with a disease-causing lesion is of critical importance in medical genetics. We explored the impact of apparently neutral common polymorphisms, using the gene encoding the urea cycle enzyme, ornithine transcarbamylase (OTC), as a model system. Distinct combinations of genetic backgrounds embracing two missense polymorphisms were created in cis with the pathogenic p.Arg40His replacement. In vitro enzymatic assays revealed that the polymorphic variants were able to modulate OTC activity both in the presence or absence of the pathogenic lesion. First, we found that the combination of the minor alleles of polymorphisms p.Lys46Arg and p.Gln270Arg significantly enhanced enzymatic activity in the wild-type protein. Second, enzymatic assays revealed that the minor allele of the p.Gln270Arg polymorphism was capable of ameliorating OTC activity when combined in cis with the pathogenic p.Arg40His replacement. Structural analysis predicted that the minor allele of the p.Gln270Arg polymorphism would serve to stabilize the OTC wild-type protein, thereby corroborating the results of the experimental assays. Our findings demonstrate the potential importance of cis-interactions between common polymorphic variants and pathogenic missense mutations and illustrate how standing genetic variation can modulate protein function.

OTC gene in ornithine transcarbamylase deficiency: clinical course and mutational spectrum in seven Korean patients.

BACKGROUND: Ornithine transcarbamylase deficiency, an inborn error of metabolism, is the most common urea cycle disorder and is caused by mutations in the OTC gene located on Xp21. In this study, the clinical and genetic characteristics of seven Korean patients with ornithine transcarbamylase deficiency were analyzed. METHODS: During 2009-2012, a total of seven patients (three male and four female patients) from six unrelated families were diagnosed with ornithine transcarbamylase deficiency by biochemical or molecular analysis. OTC gene sequencing analysis was performed in six of these patients. Clinical manifestations, clinical courses, and the results of genetic studies were reviewed retrospectively. RESULTS: The median follow-up period for the seven patients with ornithine transcarbamylase deficiency was 44 months (11.9-150 months). Clinical manifestations of ornithine transcarbamylase deficiency included vomiting and seizure, which were the most frequent signs at admission. Two of the four heterozygous female patients (50%) experienced severe neurological sequelae. The early onset male patient characterized severe neurological deficits. The late-onset male patient recovered completely from acute encephalopathy and coma without any neurological deficits. Direct sequencing and multiplex ligation-dependent probe amplification analysis of OTC gene revealed five different mutations. Of these mutations, two were novel (c.867-3T>C and c.664_667delinsAC). CONCLUSION: Ornithine transcarbamylase deficiency was genetically heterogeneous in the seven Korean patients with confirmed ornithine transcarbamylase deficiency diagnosis by biochemical findings and/or genetic analysis, together with two novel mutations in the OTC gene. We hope that these data will contribute to a better understanding of the clinical course and distinct molecular genetic characteristics of Korean patients with ornithine transcarbamylase deficiency.