Abstract
N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive disorder of the urea cycle that results from absent or decreased production of N-acetylglutamate (NAG) due to either decreased NAGS gene expression or defective NAGS enzyme. NAG is essential for the activity of carbamylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of the urea cycle. NAGSD is the only urea cycle disorder that can be treated with a single drug, N-carbamylglutamate (NCG), which can activate CPS1 and completely restore ureagenesis in patients with NAGSD. We describe a novel sequence variant NM_153006.2:c.-3026C > T in the NAGS enhancer that was found in three patients from two families with NAGSD; two patients had hyperammonemia that resolved upon treatment with NCG, while the third patient increased dietary protein intake after initiation of NCG therapy. Two patients were homozygous for the variant while the third patient had the c.-3026C > T variant and a partial uniparental disomy that encompassed the NAGS gene on chromosome 17. The c.-3026C > T sequence variant affects a base pair that is highly conserved in vertebrates; the variant is predicted to be deleterious by several bioinformatics tools. Functional assays in cultured HepG2 cells demonstrated that the c.-3026C > T substitution could result in reduced expression of the NAGS gene. These findings underscore the importance of analyzing NAGS gene regulatory regions when looking for molecular causes of NAGSD.
Highlights
High plasma glutamine and low or absent plasma citrulline[4]
Human NAGS gene regulatory region encompasses approximately 4 kb; it harbors several regions of high conservation in mammalian genomes that cluster in the NAGS promoter, immediately upstream of NAGS exon 1, and in the NAGS enhancer, which is located about 3 kb upstream of the NAGS translation initiation codon (Fig. 2A)
Human NAGS enhancer is approximately 300 bp long and binds transcription factors hepatic nuclear factor 1 (HNF1) and nuclear factor Y (NF-Y) that are important for NAGS expression in the liver (Fig. 1B and8,9)
Summary
High plasma glutamine and low or absent plasma citrulline[4]. NAGSD can arise secondary to defects in organic and fatty acid metabolism[3,4]. Most NAGSD causing sequence variants are within NAGS coding region or affect splicing of the NAGS mRNA11–15; a sequence variant in the NAGS enhancer (NM_153006.1:c.-3064 C > A) caused NAGSD by reduced NAGS expression due to decreased binding of HNF1 to its binding site[8]. We describe a novel sequence variant in the NAGS enhancer that occurred independently in two families whose members had NAGSD, totaling to three independent families with NAGS enhancer variants with apparent clinical consequences. This novel variant is pathogenic because it is associated with recurrent episodes of hyperammonemia (and epilepsy) that were promptly resolved upon treatment with NCG and caused reduced expression in a functional assay consisting of a reporter gene in cultured cells
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