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Disruption of OTC promoter‐enhancer interaction in a patient with symptoms of ornithine carbamoyltransferase deficiency
Author(s) -
Luksan Ondrej,
Jirsa Milan,
Eberova Jitka,
Minks Jakub,
Treslova Helena,
Bouckova Michaela,
Storkanova Gabriela,
Vlaskova Hana,
Hrebicek Martin,
Dvorakova Lenka
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21215
Subject(s) - enhancer , biology , promoter , microbiology and biotechnology , genetics , ornithine carbamoyltransferase , transcription factor , reporter gene , regulatory sequence , transcription (linguistics) , untranslated region , gene , gene expression , ornithine , messenger rna , arginine , amino acid , linguistics , philosophy
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 contribute 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. © 2010 Wiley‐Liss, Inc.