Clinical and structural insights into potential dominant negative triggers of proximal urea cycle disorders

Despite biochemical and genetic testing being the golden standards for identification of proximal urea cycle disorders (UCDs), genotype-phenotype correlations are often unclear. Co-occurring partial defects affecting more than one gene have not been demonstrated so far in UCDs. Here, we analyzed mutational spectrum 557 suspected UCD individuals. We probed oligomerizing forms NAGS, CPS1 OTC, evaluated surface exposure residues mutated heterozygously affected BN-PAGE gel-filtration chromatography were employed to discover protein-protein interactions within recombinant enzymes. From a total 281 confirmed patients, only 15 identified as “heterozygous-only” candidates (i.e. single defective allele). Within these cases, missense variants potentially qualify dominant negative triggers p.Gly401Arg NAGS p.Thr181Ala p.Tyr512Cys, assessed by residue oligomerization capacity exposure. However, all three seem participate critical intramolecular functions, thus, unlikely facilitate interactions. This interpretation is further supported analyses revealing no multiprotein complex formation. Collectively, analysis, structural considerations vitro experiments point against prominent role effects human