Missense mutations in codon 225 of ornithine transcarbamylase (OTC) result in decreased amounts of OTC protein: a hypothesis on the molecular mechanism of the OTC deficiency

Journal of Inherited Metabolic Disease
M A García-PérezV Rubio

Abstract

Mutations P225L and P225R were identified in codon 225 of the gene for ornithine transcarbamylase (OTC) in two patients with the neonatal form of OTC deficiency. The mutations occur at a CpG dinucleotide and eliminate a unique MspI restriction site in exon 7 of the OTC gene. They do not alter existing splice sites or create new sites, as judged from the nucleotide sequence. Both mutations are associated with undetectable levels of OTC antigen in liver homogenates, and with either complete lack of OTC activity (P225R mutation) or very small residual activity (0.15% of normal in the P225L mutation). The residual activity observed with P225L exhibits normal pH dependence, little or no increases in the Km values for ornithine and carbamoyl phosphate and normal stability at either 37 degrees C or, in the presence of 0.66 mol/L urea, at 0 degree C. The latter conditions were used to examine whether the P225L mutation favours dissociation of the active OTC trimer. Given the normal stability and lack of tendency to dissociation of the mutant enzyme, it appears likely that the dramatic reduction in the level of OTC protein is due to inefficient conversion of the mutant OTC precursor polypeptide (pOTC) into the correctly localized, appro...Continue Reading

References

Feb 1, 1988·Journal of Biochemistry·A HataI Matsuda
May 21, 1982·Biochimica Et Biophysica Acta·P BriandL Cathelineau
Nov 7, 1995·Proceedings of the National Academy of Sciences of the United States of America·V VilleretO Dideberg
Jan 1, 1994·Human Mutation·M TuchmanA A Qureshi
Jan 1, 1988·Methods in Molecular Biology·J M Walker, W Gaastra

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Citations

Jun 21, 2006·Human Mutation·Saori YamaguchiMendel Tuchman
Aug 12, 2009·Hepatology International·Ophir D KleinSeymour Packman
Jan 17, 2002·Human Mutation·Mendel TuchmanMichael G Lynch

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