Disease‐causing mutations in the promoter and enhancer of the ornithine transcarbamylase gene

The ornithine transcarbamylase (OTC) gene is on the X chromosome and its product catalyzes the formation of citrulline from ornithine and carbamylphosphate in the urea cycle. About 10%–15% of patients, clinically diagnosed with OTC deficiency (OTCD), lack identifiable mutations in the coding region...

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Bibliographic Details
Published in:	Human mutation Vol. 39; no. 4; pp. 527 - 536
Main Authors:	Jang, Yoon J., LaBella, Abigail L., Feeney, Timothy P., Braverman, Nancy, Tuchman, Mendel, Morizono, Hiroki, Ah Mew, Nicholas, Caldovic, Ljubica
Format:	Journal Article
Language:	English
Published:	United States Hindawi Limited 01-04-2018
Subjects:	Binding sites Binding Sites - genetics Citrulline Conserved sequence Deoxyribonucleic acid DNA Enhancer Elements, Genetic enhancer mutation Gene expression gene expression gene regulation Gene Expression Regulation Hepatocyte Nuclear Factor 4 - metabolism Humans hyperammonemia Inborn errors of metabolism Male Mutation Ornithine Ornithine - metabolism Ornithine Carbamoyltransferase Deficiency Disease - genetics ornithine transcarbamylase ornithine transcarbamylase deficiency promoter mutation Promoter Regions, Genetic Prospective Studies Regulatory sequences Reporter gene Retrospective Studies Splice junctions Urea urea cycle ornithine transcarbamylase deficiency enhancer mutation hyperammonemia ornithine transcarbamylase promoter mutation urea cycle gene expression gene regulation
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Summary:	The ornithine transcarbamylase (OTC) gene is on the X chromosome and its product catalyzes the formation of citrulline from ornithine and carbamylphosphate in the urea cycle. About 10%–15% of patients, clinically diagnosed with OTC deficiency (OTCD), lack identifiable mutations in the coding region or splice junctions of the OTC gene on routine molecular testing. We collected DNA from such patients via retrospective review and by prospective enrollment. In nine of 38 subjects (24%), we identified a sequence variant in the OTC regulatory regions. Eight subjects had unique sequence variants in the OTC promoter and one subject had a novel sequence variant in the OTC enhancer. All sequence variants affect positions that are highly conserved in mammalian OTC genes. Functional studies revealed reduced reporter gene expression with all sequence variants. Two sequence variants caused decreased binding of the HNF4 transcription factor to its mutated binding site. Bioinformatic analyses combined with functional assays can be used to identify and authenticate pathogenic sequence variants in regulatory regions of the OTC gene, in other urea cycle disorders or other inborn errors of metabolism. We report seven disease‐causing sequence variants, six in the promoter and one in the enhancer, in patients with clinically diagnosed ornithine transcarbamylase deficiency. Functional studies revealed reduced reporter gene expression with all sequence variants. Bioinformatic analyses combined with functional assays can be used to identify and authenticate pathogenic sequence variants in regulatory regions of the ornithine transcarbamylase gene, in other urea cycle disorders or other inborn errors of metabolism.
Bibliography:	Communicated by Johannes Zschocke Contract grant sponsor: National Institute of Diabetes Digestive and Kidney Diseases (R01DK047870, R01DK064913). ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1059-7794 1098-1004
DOI:	10.1002/humu.23394