1. Disruption of OTC promoter-enhancer interaction in a patient with symptoms of ornithine carbamoyltransferase deficiency
- Author
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Hana Vlaskova, Michaela Bouckova, Milan Jirsa, M. Hrebicek, Gabriela Storkanova, Jitka Eberova, Lenka Dvorakova, Ondrej Luksan, Jakub Minks, and Helena Trešlová
- Subjects
Male ,Untranslated region ,DNA Mutational Analysis ,Molecular Sequence Data ,Biology ,Cell Line ,Start codon ,Ornithine Carbamoyltransferase ,Genes, Reporter ,Pregnancy ,Genetics ,Humans ,Luciferases ,Promoter Regions, Genetic ,Enhancer ,Gene ,Genetics (clinical) ,Base Sequence ,Infant, Newborn ,Infant ,Promoter ,Molecular biology ,Upstream Enhancer ,Ornithine Carbamoyltransferase Deficiency Disease ,Enhancer Elements, Genetic ,Regulatory sequence ,Child, Preschool ,Mutation ,Female ,Transcription Initiation Site - Abstract
In a female patient with signs of ornithine carbamoyltransferase deficiency (OTCD), the only variation found was a heterozygous single nucleotide substitution c.-366A>G. Determination of transcription start sites of human OTC 95, 119 and 169 bp upstream of the initiation codon located the variation upstream of the 5'-untranslated region. We predicted the human promoter and enhancer elements from homology with rat and mouse, performed function analysis of both regulatory regions and assessed the impact of the promoter variation in functional studies using dual luciferase reporter assay. Our data indicate that: (i) Full transcriptional activity of human OTC promoter depends on an upstream enhancer, as do the rodent promoters. (ii) The promoter variation c.-366A>G does not affect the function of the promoter alone but it disrupts the interaction of the promoter with the enhancer. (iii) The promoter-enhancer interaction contributes to tissue specific expression of OTC in the liver. We conclude that mutations in the regulatory regions of OTC can lead to OTCD and should be included in genetic testing.
- Published
- 2010
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