Linkage disequilibrium between DNA polymorphisms within the porphobilinogen deaminase gene

Scobie, Graeme; Urquhart, Andy; Elder, George H.; Kalsheker, Noor; Llewellyn, David H.; Smyth, J. Robert; Harrison, Paul R.

doi:10.1007/bf00193188

Cited by 16 publications

(8 citation statements)

References 14 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Methodsmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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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.

et al. 1994

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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.

et al. 1994

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“…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.…”

mentioning

confidence: 99%

“…Actually, several point mutations within the PBGD gene have been identified in AIP patients with different phenotypes (6)(7)(8)(9). However, many of those mutations appear to be unique for a family.…”

mentioning

confidence: 99%

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

Lee

Anvret

1991

Proc. Natl. Acad. Sci. U.S.A.

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Molecular basis of acute intermittent porphyria: Mutations and polymorphisms in the human hydroxymethylbilane synthase gene

Astrin

Desnick²

1994

Hum. Mutat.

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Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of metabolism that results from the half-normal activity of the third enzyme in the heme biosynthetic pathway, hydroxymethylbilane synthase (HMB-synthase). AIP is an ecogenetic condition, with life-threatening acute attacks precipitated by various factors including drugs, alcohol, fasting, and certain hormones. Biochemical diagnosis is problematic and the identification of mutations in the HMB-synthase gene provides accurate detection of presymptomatic heterozygotes, permitting avoidance of the acute precipitating factors. Two HMB-synthase isozymes are encoded by the HMB-synthase gene: one unique to erythroid cells and the other a housekeeping isozyme present in all cells. These two isozymes arise from a single gene by alternative splicing. The recent isolation of the cDNAs and entire genomic sequence encoding the HMB-synthase isozymes has facilitated the detection of diagnostically useful intragenic polymorphisms and disease-causing mutations. Of the 36 mutations identified to date, most caused the classic form of AIP. These mutations included small deletions and insertions, point mutations and RNA splice junction alterations and resulted in the half-normal activity of both the erythroid-specific and housekeeping isozymes. Most AIP mutations were private; however, certain mutations were frequently found in Dutch (R116W) and Swedish (W198X) AIP families. A variant form of AIP, in which patients have normal erythroid activity, but half-normal activity of the housekeeping isozyme, resulted from two mutations at the exon 1/intron 1 boundary, each altering splicing of the hepatic-specific transcript. In addition, 10 polymorphisms in the HMB-synthase gene have been identified that are useful for the diagnosis of presymptomatic AIP heterozygotes in families whose specific mutations have not been determined.

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Linkage disequilibrium between DNA polymorphisms within the porphobilinogen deaminase gene

Cited by 16 publications

References 14 publications

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.

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.

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

Molecular basis of acute intermittent porphyria: Mutations and polymorphisms in the human hydroxymethylbilane synthase gene

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