The structure provides insights into the mechanism of action of PBGD at the molecular level and could aid the development of potential drugs for the up-regulation of PBGD activity in AIP.
Acute intermittent porphyria is an autosomal dominant inherited disorder resulting from a deficiency of porphobilinogen deaminase activity, the third enzyme in the heme biosynthesis pathway.
After excluding candidate genes within the linkage interval, we identified a nonsense mutation in the porphobilinogen deaminase gene on chromosome 11q23.3, which harbors the mutations causing acute intermittent porphyria, as the underlying genetic defect in Chester porphyria.
To date, 301 different mutations and 21 polymorphisms have been identified in the PBGD gene in AIP patients and individuals from various countries and ethnic groups.
Direct sequencing of genomic DNA samples of 11 unrelated Russian AIP patients, 32 of their relatives and 50 healthy controls from northwestern Russia including Saint Petersburg revealed nine mutations in the HMBS gene.
To study the origin of these common CpG mutations, eight intragenic single-nucleotide polymorphisms (SNPs) in the PBGD gene, as well as eight microsatellites flanking the gene in chromosome 11 were used to construct haplotypes in six AIP families of German, Polish and Swiss origins who carried either G111R (4707G>A) or R173Q (6391G>A) mutations.
Although more than 170 different mutations are known to the HMBS gene so far, over 40% of all mutations identified among the Polish AIP patients of this study are novel mutations, indicating the heterogeneity of molecular defects causing AIP.
The authors identified a novel mutation of the porphobilinogen deaminase (PBG-D) gene in a patient with acute intermittent porphyria presenting with severe and bilateral axonal radial motor neuropathy.