title: Biallelic mutations in CAD, impair de novo pyrimidine biosynthesis and decrease glycosylation precursors.
abstract: 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.
authors: Human Genetics Program, Sanford - Burnham Medical Research Institute, 10901 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
authors: Bobby G
authors: BG
authors: Ng
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director and.
authors: Lynne A
authors: LA
authors: Wolfe
authors: Human Genetics Program, Sanford - Burnham Medical Research Institute, 10901 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
authors: Mie
authors: M
authors: Ichikawa
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director and.
authors: Thomas
authors: T
authors: Markello
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19103, USA.
authors: Miao
authors: M
authors: He
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director and National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA and.
authors: Cynthia J
authors: CJ
authors: Tifft
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director and National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA and.
authors: William A
authors: WA
authors: Gahl
authors: Human Genetics Program, Sanford - Burnham Medical Research Institute, 10901 N. Torrey Pines Rd, La Jolla, CA 92037, USA hudson@sanfordburnham.org.
authors: Hudson H
authors: HH
authors: Freeze
mesh_terms: D000818:Animals; D001221:Aspartate Carbamoyltransferase / Q000235:genetics*; D001483:Base Sequence; D016466:CHO Cells; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics*; D002675:Child, Preschool; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D004080:Dihydroorotase / Q000235:genetics*; D056726:Genetic Association Studies; D006031:Glycosylation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000175:diagnosis* / Q000235:genetics; D020125:Mutation, Missense; D011499:Protein Processing, Post-Translational; D011743:Pyrimidines / Q000096:biosynthesis*; D017384:Sequence Deletion
chemical_list: C033626:CAD trifunctional enzyme; D011743:Pyrimidines; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); C030986:pyrimidine