Haplotype analysis of Norwegian and Swedish patients with acute intermittent porphyria (AIP): Extreme haplotype heterogeneity for the mutation R116W

Abstract. Acute intermittent porphyria (AIP), the most common of the acute porphyrias, is caused by mutations in the gene encoding hydroxymethylbilane synthase (HMBS) also called porphobilinogen deaminase (PBGD). The mutation spectrum in the HMBS gene is characterized by a majority of family specific mutations. Among the exceptions are R116W and W198X, with high prevalence in both the Dutch and Swedish populations. These two mutations were also detected in unrelated Norwegian patients. Thus, Norwegian and Swedish patients were haplotyped using closely linked flanking microsatellites and intragenic single nucleotide polymorphisms (SNPs) to see if the high frequency of these two mutations is due to a founder effect. Twelve intragenic SNPs were determined by a method based on fluorescent restriction enzyme fingerprinting single-strand conformation polymorphism (F-REF-SSCP). W198X occurred exclusively on one haplotype in both Norwegian and Swedish patients, showing that it has originated from a common gene source. In contrast, R116W was found on three different haplotypes in three Norwegian families, and in five Swedish families on four or five haplotypes. This extreme haplotype heterogeneity indicates that R116W is a recurrent mutation, maybe explained by the high mutability of CpG dinucleotides. This can also explain why it is the only AIP mutation reported to occur in seven different populations (Norway

Mutations in Acute Intermittent Porphyria Detected by ELISA Measurement of Porphobilinogen Deaminase

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Effects of Administration of Antioxidants in Acute Intermittent Porphyria

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Partial protoporphyrinogen oxidase (<it>PPOX</it>) gene deletions, due to different <it>Alu</it>-mediated mechanisms, identified by MLPA analysis in patients with variegate porphyria

<p>Abstract</p> <p>Variegate porphyria (VP) is an autosomal dominantly inherited hepatic porphyria. The genetic defect in the <it>PPOX</it> gene leads to a partial defect of protoporphyrinogen oxidase, the penultimate enzyme of heme biosynthesis. Affected individuals can develop cutaneous symptoms in sun-exposed areas of the skin and/or neuropsychiatric acute attacks. The identification of the genetic defect in VP families is of crucial importance to detect the carrier status which allows counseling to prevent potentially life threatening neurovisceral attacks, usually triggered by factors such as certain drugs, alcohol or fasting.</p> <p>In a total of 31 Swedish VP families sequence analysis had identified a genetic defect in 26. In the remaining five families an extended genetic investigation was necessary. After the development of a synthetic probe set, MLPA analysis to screen for single exon deletions/duplications was performed.</p> <p>We describe here, for the first time, two partial deletions within the <it>PPOX</it> gene detected by MLPA analysis. One deletion affects exon 5 and 6 (c.339-197_616+320del1099) and has been identified in four families, most probably after a founder effect. The other extends from exon 5 to exon 9 (c.339-350_987+229del2609) and was found in one family. We show that both deletions are mediated by <it>Alu</it> repeats.</p> <p>Our findings emphasize the usefulness of MLPA analysis as a complement to <it>PPOX</it> gene sequencing analysis for comprehensive genetic diagnostics in patients with VP.</p

Haplotype Analysis of Norwegian and Swedish Patients with Acute Intermittent Porphyria (AIP): Extreme Haplotype Heterogeneity for the Mutation R116W

Acute intermittent porphyria (AIP), the most common of the acute porphyrias, is caused by mutations in the gene encoding hydroxymethylbilane synthase (HMBS) also called porphobilinogen deaminase (PBGD). The mutation spectrum in the HMBS gene is characterized by a majority of family specific mutations. Among the exceptions are R116W and W198X, with high prevalence in both the Dutch and Swedish populations. These two mutations were also detected in unrelated Norwegian patients. Thus, Norwegian and Swedish patients were haplotyped using closely linked flanking microsatellites and intragenic single nucleotide polymorphisms (SNPs) to see if the high frequency of these two mutations is due to a founder effect. Twelve intragenic SNPs were determined by a method based on fluorescent restriction enzyme fingerprinting single-strand conformation polymorphism (F-REF-SSCP)

Acute Intermittent Porphyria: Diagnostic Conundrums

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Markers for Vulnerability in Acute Porphyria. A Hypothesis Paper

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Liver Transplantation in a Boy with Acute Porphyria Due to Aminolaevulinate Dehydratase Deficiency

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A recurrent mutation in variegate porphyria patients from Chile and Sweden: Evidence for a common genetic background?

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