Journal
HUMAN MOLECULAR GENETICS
Volume 24, Issue 11, Pages 3050-3057Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv057
Keywords
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Funding
- Rocket Fund
- National Institutes of Health (NIH) [R01DK099551, R01DK55615]
- Common Fund of the Office of the Director, NIH
- Intramural Research Program of the National Human Genome Research Institute
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In mitochondria, carbamoyl-phosphate synthetase 1 activity produces carbamoyl phosphate for urea synthesis, and deficiency results in hyperammonemia. Cytoplasmic carbamoyl-phosphate synthetase 2, however, is part of a tri-functional enzyme encoded by CAD; no human disease has been attributed to this gene. The tri-functional enzyme contains carbamoyl-phosphate synthetase 2 (CPS2), aspartate transcarbamylase (ATCase) and dihydroorotase (DHOase) activities, which comprise the first three of six reactions required for de novo pyrimidine biosynthesis. Here we characterize an individual who is compound heterozygous for mutations in different domains of CAD. One mutation, c.1843-1G > A, results in an in-frame deletion of exon 13. The other, c.6071G > A, causes a missense mutation (p.Arg2024Gln) in a highly conserved residue that is essential for carbamoyl-phosphate binding. Metabolic flux studies showed impaired aspartate incorporation into RNA and DNA through the de novo synthesis pathway. In addition, CTP, UTP and nearly all UDP-activated sugars that serve as donors for glycosylation were decreased. Uridine supplementation rescued these abnormalities, suggesting a potential therapy for this new glycosylation disorder.
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