Three splicing defects (IVS1+3G-->T, 86A-->T, IVS13-2A-->G), an insertion (416insCA), and two missense mutations (664G-->A and 833T-->G) in the porphobilinogen deaminase (PBGD) gene were identified in six unrelated Finnish patients with acute intermittent porphyria (AIP).
To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype.
Porphobilinogen deaminase mutants that cause acute intermittent porphyria have been investigated as recombinant proteins expressed in Escherichia coli, yielding important insight into the mechanism of dipyrromethane cofactor assembly and tetrapyrrole chain polymerization.
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.
Acute intermittent porphyria has hitherto been recognised as an autosomal dominant inborn error of haem metabolism characterised by a depressed activity of the enzyme uroporphyrinogen I synthase (URO.S).
Since biochemical diagnosis is problematic, the identification of hydroxymethylbilane synthase mutations has facilitated the detection of AIP heterozygotes.
A mouse model that is partially deficient in PBGD and biochemically mimics AIP after induction of the hepatic ALA synthase by phenobarbital was used in this study to identify the site of formation of the presumably toxic porphyrin precursors and study the effect of enzyme-replacement therapy by using recombinant human PBGD (rhPBGD).
The three-dimensional structures of mutants of porphobilinogen deaminase: toward an understanding of the structural basis of acute intermittent porphyria.
Molecular analysis of the hydroxymethylbilane synthase (HMBS) gene in Italian patients with acute intermittent porphyria: report of four novel mutations.
AIP is diagnosed on the basis of characteristic clinical symptoms, elevated levels of urinary porphyrin precursors aminolevulinic acid (ALA) and porphobilinogen (PBG) and a decreased erythrocytic HMBS activity, although an identifiable HMBS mutation provides the ultimate proof for AIP.
This study demonstrates that in vitro characterization of missense variations in the HMBS gene can provide valuable information for the interpretation of clinical, biochemical and genetic data, for establishing a diagnosis of AIP.
We developed recombinant adeno-associated virus (rAAV) vectors expressing human PBGD protein driven by a liver-specific promoter to provide sustained protection against induced attacks in a predictive model for AIP.
A novel 55-basepair deletion of hydroxymethylbilane synthase gene found in a Chinese patient with acute intermittent porphyria and her family: A case report.