Non-coding sequence variants define a novel regulatory element in the
first intron of the N-acetylglutamate synthase gene.
N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an
autosomal recessive urea cycle disorder caused either by decreased
expression of the NAGS gene or defective NAGS enzyme resulting in
decreased production of N-acetylglutamate (NAG), an allosteric activator
of carbamylphosphate synthetase 1 (CPS1). NAGSD is the only urea cycle
disorder that can be effectively treated with a single drug,
N-carbamylglutamate (NCG), a stable NAG analog, which activates CPS1 to
restore ureagenesis. We describe three patients with NAGSD due to four
novel sequence variants in the NAGS regulatory regions. All three
patients had hyperammonemia that resolved upon treatment with NCG.
Sequence variants NM_153006.2:c.-3065A>C and
NM_153006.2:c-3098C>T reside in the NAGS enhancer, within
known HNF1 and predicted glucocorticoid receptor binding sites,
respectively. Sequence variants NM_153006.2:c.426+326G>A
and NM_153006.2:c.427-218A>C reside in the first intron of
NAGS and define a novel NAGS regulatory element that binds retinoic X
receptor α. Reporter gene assays in HepG2 and HuH-7 cells demonstrated
that all four substitutions could result in reduced expression of NAGS.
These findings show that analyzing non-coding regions of NAGS and other
urea cycle genes can reveal molecular causes of disease and identify
novel regulators of ureagenesis.