Mutation Analysis of the Ornithine Transcarbamylase (OTC) Gene in Five Japanese OTC Deficiency Patients Revealed Two Known and Three Novel Mutations Including a Deep Intronic Mutation

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Ornithine transcarbamylase (OTC) deficiency is the most common inborn error ofthe urea cycle. Although a combination of molecular methods have been usedincluding DNA sequencing of all 10 exons and exon-intron boundaries of OTC gene,only ~80% of patients with OTC deficiency are found to have mutations. We reporttwo known and three novel mutations of the OTC gene in five Japanese patientsincluding two neonatal-onset, one late-onset, and two symptomatic female patients.Known nonsense mutations (c.578G>A and c.421C>T) were detected in aneonatal-onset male and a symptomatic female patient, respectively. Mutationanalysis revealed two novel mutations including one splice site mutation (c.386+1G>C)in a symptomatic female patient and one missense mutation (c.515T>A) in a late-onsetmale patient. In the remaining case, which was a neonatal-onset male patient, nomutation was disclosed by direct sequencing of all 10 exons and their flanking intronsequences. Therefore, OTC mRNA in the liver was analyzed by RT-PCR, andremarkably, a 135-nt insertion was detected between exons 5 and 6. Genomic DNAanalysis of intron sequences revealed a single nucleotide change at 265 bp downstreamfrom the 3' end of exon 5, which created the novel splice acceptor site. Thereby, a135-nt exon was created from the central part of an intron sequence. This is the firstreport of mutation deep in the intronic sequence in the OTC gene. Molecular analysisusing genomic DNA and mRNA will increase the mutation detection ratio in the OTCgene.
神戸大学の論文

Mutation Analysis of the Ornithine Transcarbamylase (OTC) Gene in Five Japanese OTC Deficiency Patients Revealed Two Known and Three Novel Mutations Including a Deep Intronic Mutation

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