Two different point G to A mutations in exon 10 of the porphobilinogen deaminase gene are responsible for acute intermittent porphyria.

Abstract

Two mutations of the porphobilinogen (PBG) deaminase gene resulting in cross-reacting immunological material (CRIM) positive forms of acute intermittent porphyria (AIP) have been identified by in vitro amplification of cDNA and cloning of the amplified products in a bacterial expression vector. Both mutations resulted from G to A transitions in exon 10 of the gene and produced arginine to glutamine substitutions in the abnormal protein. Expression of mutant cDNA in Escherichia coli reveals that one but not the other of these amino acid changes results in a striking decrease of the optimal pH of the mutated enzyme. One or the other of these two mutations accounted for the defect causing AIP in six unrelated patients among the eight patients evaluated with the CRIM positive subtype of this disorder. (J. Clin. Invest. 1990Invest. . 86:1511Invest. -1516

Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene. An initiation codon missense mutation in the housekeeping transcript causes "variant acute intermittent porphyria" with normal expression of the erythroid-specific enzyme.

“…The identification and characterization of the mutations in the HMB-synthase gene causing ALP have increased our understanding of the molecular basis of variant AEP (22, 23), identified the molecular heterogeneity underlying both the classical and variant forms (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41), permitted the precise diagnosis of asymptomatic heterozygotes (22,23,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41), and opportunity for structure-function correlations of the human enzyme. Here, six new mutations in the HMB-synthase gene are described which further increase our understanding of the molecular basis of AIP and the synthesis, structure, and function of this heme biosynthetic enzyme.…”

“…Lymphoid cell lines were established and maintained as described previously (52). From each proband, erythrocyte lysates were assayed for HMB-synthase activity (21) and genomic DNA was extracted from peripheral blood (53,54) for detection of known HMB-synthase mutations (IVSI-1, IVSI+1, Q15SX, R167Q, R167W, R173Q, W198X, and IVSI2-1) as described previously (29)(30)(31)(32)(33)(34)(35).…”

“…cDNAs encoding the 42-kD housekeeping and 40-kD erythroidspecific isozymes, which differ only in their NH2-terminal amino acid sequences, have been isolated and characterized (12,15). The enzyme from human erythrocytes has been purified to homogeneity and its physical and kinetic properties have been determined (16 (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). However, mutations W198X and R116W have been detected in a large number of Swedish and Dutch AIP families, respectively (33,40).…”

Identification of the most common mutation within the porphobilinogen deaminase gene in Swedish patients with acute intermittent porphyria.

“…Four intragenic restriction fragment length polymorphisms (Msp I, Pst I, BstNI, and ApaLI) in the PBGD gene have been successfully used for haplotype analysis including carrier detection in AIP families (3)(4)(5). Several point mutations of the PBGD gene have been identified in phenotypically different AIP patients (6)(7)(8)(9). However, none ofthe mutations so far identified has been found to occur more frequently than any of the others.…”

A point mutation, C to T, in exon 8 of the porphobilinogen deaminase gene in a Japanese family with acute intermittent porphyria

“…To date, more than 30 different mutations have been reported (Daimon et al, 1993(Daimon et al, , 1994Delfau et al, 1990Delfau et al, , 1991Grandchamp et al, 1989a-c;Gu et al, 1992Gu et al, , 1994Scobie et al, 1990;Lee and Anvret, 1991;Lee et al, 1990;Llewellyn et al, 1992;Lundin et al, 1994;Mgone et al, 1992Mgone et al, , 1993Schreiber et al, 1994). Although high prevalences have been reported for two mutations as the result of a founder effect (Lee et al, 1990;Lee and Anvret, 1991 ;Gu et al, 1993), many of them were found only in very few families, indicating that AIP is very heterogeneous at the molecular level.…”