Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1.
BACKGROUND
Mutations of the AGXT gene encoding the alanine:glyoxylate aminotransferase liver enzyme (AGT) cause primary hyperoxaluria type 1 (PH1). Here we report a molecular modeling study of selected missense AGXT mutations: the common Gly170Arg and the recently described Gly47Arg and Ser81Leu variants, predicted to be pathogenic using standard criteria.


METHODS
Taking advantage of the refined 3D structure of AGT, we computed the dimerization energy of the wild-type and mutated proteins.


RESULTS
Molecular modeling predicted that Gly47Arg affects dimerization with a similar effect to that shown previously for Gly170Arg through classical biochemical approaches. In contrast, no effect on dimerization was predicted for Ser81Leu. Therefore, this probably demonstrates pathogenic properties via a different mechanism, similar to that described for the adjacent Gly82Glu mutation that affects pyridoxine binding.


CONCLUSIONS
This study shows that the molecular modeling approach can contribute to evaluating the pathogenicity of some missense variants that affect dimerization. However, in silico studies--aimed to assess the relationship between structural change and biological effects--require the integrated use of more than 1 tool.
Robbiano
Angela
A
Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole, Orbassano, Italy.
Frecer
Vladimir
V
Miertus
Jan
J
Zadro
Cristina
C
Ulivi
Sheila
S
Bevilacqua
Elena
E
Mandrile
Giorgia
G
De Marchi
Mario
M
Miertus
Stanislav
S
Amoroso
Antonio
A
D000595:Amino Acid Sequence; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D055503:Protein Multimerization; D000637:Transaminases / Q000737:chemistry / Q000235:genetics*
D000637:Transaminases; C019635:Alanine-glyoxylate transaminase