Disruption of OTC promoter-enhancer interaction in a patient with symptoms of ornithine carbamoyltransferase deficiency.
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.
Luksan
Ondrej
O
Laboratory of Experimental Hepatology, Institute for Clinical and Experimental Medicine, Prague.
Jirsa
Milan
M
Eberova
Jitka
J
Minks
Jakub
J
Treslova
Helena
H
Bouckova
Michaela
M
Storkanova
Gabriela
G
Vlaskova
Hana
H
Hrebicek
Martin
M
Dvorakova
Lenka
L
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
D008156:Luciferases; D009954:Ornithine Carbamoyltransferase