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

Abstract

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

Understanding carbamoyl phosphate synthetase (CPS1) deficiency by using the recombinantly purified human enzyme: Effects of CPS1 mutations that concentrate in a central domain of unknown function

“…Interestingly, the UFSD has been found to host missense mutations in CPS1D patients (Fig. 1C,D) with rather high frequency [2], suggesting an important and until now unclear role of this domain.…”

“…CPS1D has been associated with a relatively large number of different, generally "private" mutations which occur in single families with very little recurrence [2]. Many of the >130 missense mutations reported in CPS1D remain to be proven responsible for the deficiency.…”

“…Primary CPS1 deficiency (CPS1D; MIM #237300), a recessively inherited urea cycle disease leading to frequently fatal hyperammonemia [1,2], is due to mutations in the CPS1 gene. This gene, located in 2q35 [3] and being composed of 38 exons and 37…”

Cell and Gene Therapy for Carbamoyl Phosphate Synthetase 1 Deficiency

“…Most monogenic disorders only have very rare cases; however, they have variable mutations for single genes. In fact, more than 90% of the known CPS1 mutations are private [14].…”

Stable isotopes in the diagnosis and treatment of inherited hyperammonemia

“…However, pathological mutations are not always identified [23,24] and even when they are found, they may not provide much prognostic information, especially in the case of heterozygotes of OTC deficiency, the most common urea cycle disorder [25]. This may result in some scenarios where the non-invasive determination of urea cycle function can greatly contribute to clinical management.…”