Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations.
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.
University Children's Hospital Zurich, Division of Metabolism, Zurich, Switzerland. Johannes.Haeberle@kispi.uzh.ch
Johannes
J
Häberle
Oleg A
OA
Shchelochkov
Jing
J
Wang
Panagiotis
P
Katsonis
Lynn
L
Hall
Sara
S
Reiss
Angela
A
Eeds
Alecia
A
Willis
Meeta
M
Yadav
Samantha
S
Summar
Olivier
O
Lichtarge
Vicente
V
Rubio
Lee-Jun
LJ
Wong
Marshall
M
Summar
D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000737:chemistry / Q000235:genetics*; D020165:Carbamoyl-Phosphate Synthase I Deficiency Disease / Q000175:diagnosis* / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics*; D054643:INDEL Mutation / Q000235:genetics; D008956:Models, Chemical; D020125:Mutation, Missense / Q000235:genetics; D011487:Protein Conformation; D020033:Protein Isoforms / Q000235:genetics
D018389:Codon, Nonsense; D020033:Protein Isoforms; D002222:Carbamoyl-Phosphate Synthase (Ammonia)