A point mutation G—A in exon 12 of the porphoblllnogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria

Grandchamp, Bernard; Picat, Christiane; Rooij, Felix de; Beaumont, Carole; Wilson, Peter J.; Deybach, Jean Charles; Nordmann, Y

doi:10.1093/nar/17.16.6637

Cited by 113 publications

(56 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most naturally occurring mutations at 5' consensus sequences inactivate the authentic 5' splice-site and abolish normal splicing. Certain mutations cause an exon to be skipped during RNA splicing (6)(7)(8). However, exon skipping due to a deletion mutation within a nonconsensus exon sequence has never been reported.…”

Section: Introductionmentioning

confidence: 99%

Exon skipping during splicing of dystrophin mRNA precursor due to an intraexon deletion in the dystrophin gene of Duchenne muscular dystrophy kobe.

Matsuo¹,

Masumura²,

Nishio³

et al. 1991

J. Clin. Invest.

136

View full text Add to dashboard Cite

Recent molecular studies have shown that in a patient with Duchenne muscular dystrophy (DMD) Kobe, the size of exon 19 of the dystrophin gene was reduced to 36 bp due to the deletion of 52 bp out of 88 bp of the exon. The consensus sequences at the 5' and 3' splice sites of exon 19 were unaltered (Matsuo, M., et al. 1990. Biochem. Biophys. Res. Commun. 170:963-967). To further elucidate the molecular nature of the defect, we examined the primary structure of cytoplasmic dystrophin mRNA of the DMD Kobe patient across the junctions of exons 18, 19, and 20 by gel electrophoresis and sequencing of polymerase chain reaction-amplified cDNA. The mRNA coding for dystrophin was reverse transcribed using random primers, and the cDNA was then enzymatically amplified in vitro. The targeted fragment was smaller than expected from the genomic DNA analysis. By sequencing of the amplified product, we found that exon 18 was joined directly to exon 20, so that exon 19 was completely absent, suggesting that this exon was skipped during processing of the dystrophin mRNA precursor. All other bases in the amplified product were unaltered. Therefore, the data strongly suggest that the internal exon deletion generates an abnormally spliced mRNA in which the sequence of exon 18 is joined to the sequence of exon 20. We propose that the deletion is responsible for abnormal processing of the DMD Kobe allele. This finding has important implications regarding the determinants of a functional splice site. (J. Clin.

show abstract

Section: Introductionmentioning

confidence: 99%

Exon skipping during splicing of dystrophin mRNA precursor due to an intraexon deletion in the dystrophin gene of Duchenne muscular dystrophy kobe.

Matsuo¹,

Masumura²,

Nishio³

et al. 1991

J. Clin. Invest.

136

View full text Add to dashboard Cite

show abstract

“…Among the seven enzymes in the heme biosynthetic pathway that are implicated in inherited defects of heme biosynthesis, molecular defects have been analyzed in four: i.e., 8-aminolevulinate dehydratase (7), porphobilinogen deaminase (8,9), uroporphyrinogen III cosynthase (10), and uroporphyrinogen decarboxylase (11). Molecular analysis has not yet been reported for the remaining three enzymes, including the ferrochelatase defect in EPP.…”

mentioning

confidence: 99%

The molecular defect of ferrochelatase in a patient with erythropoietic protoporphyria.

Nakahashi¹,

Fujita²,

Taketani³

et al. 1992

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

View full text Add to dashboard Cite

The molecular basis of an inherited defect of ferrochelatase in a patient with erythropoietic protoporphyria (EPP) was investigated. Ferrochelatase is the terminal enzyme in the heme biosynthetic pathway and catalyzes the insertion of ferrous iron into protoporphyrin IX to form heme. In EpsteinBarr virus-transformed lymphoblastoid cells from a proband with EPP, enzyme activity, an immunochemically quantifiable protein, and mRNA content of ferrochelatase were about one-half the normal level. In contrast, the rate of ftrnription of ferrochelatase mRNA in the proband's cells was normal, suggesting that decreased ferrochelatase mRNA is due to an unstable transcript. cDNA clones encoding ferrochelatase in the proband, isolated by amplification using the polymerase chain reaction, were found to be classifid either into those encoding the normal protein or into those encoding an abnormal protein that lacked exon 2 of the ferrochelatase gene, indicating that the proband is heterozygous for the ferrochelatase defect. Genomic DNA analysis revealed that the abnormal allele had a point mutation, C -* T, near the acceptor site of intron 1. This point mutation appears to be responsible for the post-transcriptional splicing abnormality resulting in an aberrant transcript of ferrochelatase in this patient.

show abstract

“…Since 1989 (Grandchamp et al 1989), many different mutations associated with AIP have been detected in the HMBS gene, including deletions, insertions, and missense, nonsense, and splicing mutations. The mutations are scattered throughout the gene from exon 1 to exon 15, but nearly onehalf of them are found in exons 10 and 12.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding the abnormalities of the HMBS gene, more than 150 different mutations have been reported since 1989 (Grandchamp et al 1989). In Japan, however, molecular analyses have been documented in only six families (Daimon et al 1993;Daimon et al 1994;Morita et al 1995;Tomie et al 1998;Maeda et al 1999) to date.…”

Section: Introductionmentioning

confidence: 99%

Two deletion mutations in the hydroxymethylbilane synthase gene in two unrelated Japanese patients with acute intermittent porphyria

et al. 2000

View full text Add to dashboard Cite

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease caused by a decreased activity of hydroxymethylbilane synthase (HMBS). Regarding the abnormalities of the HMBS gene, many different mutations have been reported worldwide; however, few families from Japan have been studied. In this work, we investigated the presence of mutations in two unrelated Japanese patients with AIP. Mutational analysis was performed using the polymerase chain reaction-single strand conformation polymorphism (SSCP) method, followed by DNA sequencing. Reliable restriction enzyme cleavage assays were also established for the pedigree analyses. Unique SSCP patterns were noted in exons 12 and 15 of the HMBS gene. Sequencing revealed different mutations in each patient: a two-base deletion of CT at nucleotide 730-731 (730delCT), and also a two-base deletion of CA at position 982-983 (982delCA). Both of the deletion mutations lead to truncated proteins with an abnormal C-terminus, which would be expected to decrease the stability and/or activity of HMBS. Using the cleavage assays, we were able to definitively identify gene carriers in the family. This study adds a novel mutation to those that have been previously reported, and emphasizes that molecular analysis would be very useful not only for the identification of asymptomatic gene carriers in the family but also for the detection of ancestral founders in porphyria families.

show abstract

A point mutation G—A in exon 12 of the porphoblllnogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria

Cited by 113 publications

References 21 publications

Exon skipping during splicing of dystrophin mRNA precursor due to an intraexon deletion in the dystrophin gene of Duchenne muscular dystrophy kobe.

Exon skipping during splicing of dystrophin mRNA precursor due to an intraexon deletion in the dystrophin gene of Duchenne muscular dystrophy kobe.

The molecular defect of ferrochelatase in a patient with erythropoietic protoporphyria.

Two deletion mutations in the hydroxymethylbilane synthase gene in two unrelated Japanese patients with acute intermittent porphyria

Contact Info

Product

Resources

About