title: Disruption of OTC promoter-enhancer interaction in a patient with symptoms of ornithine carbamoyltransferase deficiency.
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.
authors.affiliation: Laboratory of Experimental Hepatology, Institute for Clinical and Experimental Medicine, Prague.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Luksan
authors.forename: Milan
authors.initials: M
authors.lastname: Jirsa
authors.forename: Jitka
authors.initials: J
authors.lastname: Eberova
authors.forename: Jakub
authors.initials: J
authors.lastname: Minks
authors.forename: Helena
authors.initials: H
authors.lastname: Treslova
authors.forename: Michaela
authors.initials: M
authors.lastname: Bouckova
authors.forename: Gabriela
authors.initials: G
authors.lastname: Storkanova
authors.forename: Hana
authors.initials: H
authors.lastname: Vlaskova
authors.forename: Martin
authors.initials: M
authors.lastname: Hrebicek
authors.forename: Lenka
authors.initials: L
authors.lastname: Dvorakova
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004742:Enhancer Elements, Genetic; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009954:Ornithine Carbamoyltransferase / Q000235:genetics*; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000201:enzymology* / Q000235:genetics*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D024363:Transcription Initiation Site
chemical_list: D008156:Luciferases; D009954:Ornithine Carbamoyltransferase