Residual activity of human porphobilinogen deaminase with R167Q or R167W mutations: an explanation for survival of homozygous and compound heterozygous acute intermittent porphyrics. |
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Authors: | A Edixhoven-Bosdijk F W M de Rooij E de Baar-Heesakkers J H P Wilson |
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Institution: | Department of Internal Medicine, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. |
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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. |
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