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The Transcriptional Regulation of N‐Acetylglutamate Synthase and a Mutation in the Enhancer of the NAGS Gene
Author(s) -
Heibel Sandra Kirsch,
AhMew Nicholas,
Nissim Itzhak,
Yudkoff Marc,
Tuchman Mendel,
Caldovic Ljubica
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.564.4
Subject(s) - enhancer , atp synthase , gene , genetics , mutation , chemistry , biology , gene expression
The urea cycle converts toxic ammonia to urea within the liver in mammals. As the first enzyme involved in urea synthesis, N‐acetylglutamate synthetase (NAGS), catalyzes the formation of an essential cofactor for carbamylphosphate synthetase I (CPSI), the first enzyme to sequester ammonia. NAGS deficiency is a rare but highly treatable urea cycle disorder. We have identified a promoter region and enhancer region of NAGS and confirmed that transcription factors Sp1 and CREB bind to the promoter and HNF1 and NF‐Y bind to the enhancer. A patient with a biochemical profile consistent with a NAGS deficiency, and no deleterious mutations in the exons and intron/exon boundaries of NAGS failed to detect mutations, was homozygous for a mutation in the HNF1 binding site of the recently identified enhancer. The mutation is recessive and carried by the patient's parents. Genotyping a cohort of 500 subjects failed to identify the mutated allele. Additional functional studies are underway to examine the regulatory role of this binding site in NAGS transcription and the effects of this mutation. Results show that NAGS transcription is regulated through cis‐acting elements within the promoter and enhancer regions and may identify the first urea cycle disorder due to a mutation in a regulatory region. Taken together, we demonstrate the importance of collaborative basic science and clinical research.