title: Residual activity of human porphobilinogen deaminase with R167Q or R167W mutations: an explanation for survival of homozygous and compound heterozygous acute intermittent porphyrics.
abstract: To find an explanation for survival of homozygous or compound heterozygous variants of acute intermittent porphyria, we studied the three mutant forms of porphobilinogen deaminase (PBG-d) described in the four reported patients with homozygous acute intermittent porphyria. Wild-type human PBG-d and the PBG-d R167W, R167Q and R173Q mutants were expressed in Escherichia coli and the recombinant mutant human enzyme were examined for enzyme activity. Specific antibodies against human PBG-d detected the three human PBG-d mutants. All three had less than 2% of wild-type enzyme activity when examined under customary assay conditions (pH 8.0), but the R167W and R167Q mutants were found to have about 25% of normal activity when assayed at pH 7.0. This residual activity at a more physiological pH provides an explanation for survival when these mutations are inherited in a homozygous or compound heterozygous fashion.
authors.affiliation: Department of Internal Medicine, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Edixhoven-Bosdijk
authors.forename: F W M
authors.initials: FW
authors.lastname: de Rooij
authors.forename: E
authors.initials: E
authors.lastname: de Baar-Heesakkers
authors.forename: J H P
authors.initials: JH
authors.lastname: Wilson
mesh_terms: D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006863:Hydrogen-Ion Concentration; D011163:Hydroxymethylbilane Synthase / Q000235:genetics* / Q000378:metabolism*; D007525:Isoelectric Focusing; D008099:Liver / Q000378:metabolism; D009154:Mutation; D017118:Porphyria, Acute Intermittent / Q000235:genetics* / Q000401:mortality*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D011163:Hydroxymethylbilane Synthase