Biallelic mutations in CAD, impair de novo pyrimidine biosynthesis and decrease glycosylation precursors

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Mitochondrial carbamoyl-phosphate synthetase 1 (CPS1) is crucial for urea synthesis; its deficiency causes hyperammonemia.
• Cytoplasmic carbamoyl-phosphate synthetase 2 (CPS2) is part of the trifunctional enzyme CAD, essential for de novo pyrimidine biosynthesis.
• No human diseases were previously linked to the CAD gene.

Observation:

• A patient presented with compound heterozygous mutations in the CAD gene.
• One mutation (c.1843-1G>A) caused an in-frame deletion of exon 13.
• The second mutation (c.6071G>A) resulted in a missense change (p.Arg2024Gln) affecting carbamoyl-phosphate binding.

Findings:

• Metabolic flux studies revealed impaired aspartate incorporation into RNA and DNA via the de novo pyrimidine pathway.
• Levels of CTP, UTP, and most UDP-activated sugars essential for glycosylation were significantly decreased.
• The observed metabolic abnormalities were reversed by uridine supplementation.

Implications:

• This study identifies a new human disease associated with the CAD gene, leading to a novel glycosylation disorder.
• The findings highlight the critical role of the CAD gene in both pyrimidine biosynthesis and glycosylation.
• Uridine supplementation demonstrates potential as a therapeutic strategy for this newly identified disorder.