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Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations
Author(s) -
Häberle Johannes,
Shchelochkov Oleg A.,
Wang Jing,
Katsonis Panagiotis,
Hall Lynn,
Reiss Sara,
Eeds Angela,
Willis Alecia,
Yadav Meeta,
Summar Samantha,
Lichtarge Olivier,
Rubio Vicente,
Wong LeeJun,
Summar Marshall
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21406
Subject(s) - missense mutation , biology , gene , genetics , nonsense mutation , allosteric regulation , mutation , receptor
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. Hum Mutat 32:1–11, 2011. © 2011 Wiley‐Liss, Inc.