Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations

摘要: Deficiency of carbamoyl phosphate synthetase I (CPSI) results in hyperammonemia ranging from neonatally lethal to environmentally induced adult-onset disease. Over 24 years, analysis tissue and DNA samples 205 unrelated individuals diagnosed with CPSI deficiency (CPSID) detected 192 unique CPS1 gene changes, which 130 are reported here for the first time. Pooled already mutations, they constitute a total 222 including 136 missense, 15 nonsense, 50 changes other types resulting enzyme truncation, 21 causing in-frame alterations. Only ∼10% mutations recur families, predominantly affecting CpG dinucleotides, further complicating diagnosis because "private" nature such mutations. Missense unevenly distributed along gene, highlighting existence regions having greater functional importance than regions. We exploit crystal structure allosteric domain rationalize effects it. Comparative modeling is used create structural model remainder enzyme. found directly correlate, respectively, one-residue evolutionary inversely correlate solvent accessibility mutated residue. This large-scale report spanning wide variety molecular defects important this protein.