Detection of seven point mutations in the porphobilinogen deaminase gene in patients with acute intermittent porphyria, by direct sequencing of in vitro amplified cDNA.
This study highlights differences both in PBGD gene mutations causing AIP and in SNPs between white and black peoples; the allele frequencies provided contribute to a better knowledge of the variability of these markers among the major population groups, especially in sub-Saharan West African and Afro-Caribbean populations.
Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease.
Since 1966, we have studied all known Finnish AIP patients (n = 196) and their families (n = 45) and identified the porphobilinogen deaminase (PBGD) mutation in each family.
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.
Identification of two novel mutations in the hydroxymethylbilane synthase gene in three patients from two unrelated families with acute intermittent porphyria.
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).
Detection of DNA variations by molecular techniques allows a diagnosis of acute intermittent porphyria in situations where the measurement of porphyrins and precursors in urine and faeces and erythrocyte hydroxymethylbilane synthase activity is inconclusive.
DNA analyses of the family members revealed that conventional assays of erythrocyte PBGD activity identified correctly only 72% of the carriers for the AIP mutation.
The diagnostic efficiency of biochemical assays versus mutation screening in the PBGD gene was studied in three large AIP families, each representing different CRIM subtypes of 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.
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).