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

Nakahashi, Yoshitsugu; Fujita, Hideaki; Taketani, Shigeru; Ishida, Nobuhiro; Kappas, Attallah; Sassa, Shigeru

doi:10.1073/pnas.89.1.281

Cited by 76 publications

(38 citation statements)

References 32 publications

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“…Previously reported mutations in or near putative branchpoint regions of human premRNA were shown to be associated with the use of alternative splice sites (9,30), enhanced efficiency of splicing (31) or exon skipping (32). We investigated, therefore, whether the observed intron retention also occurred in our index patient and identified two LCAT mRNA species in her leukocytes: a product of a size that would be expected after correct splicing of intron sequence, and a larger mutant product.…”

Section: Discussionmentioning

confidence: 99%

An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease).

Kuivenhoven¹,

Weibusch²,

Pritchard³

et al. 1996

J. Clin. Invest.

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The first step in the splicing of an intron from nuclear precursors of mRNA results in the formation of a lariat structure. A distinct intronic nucleotide sequence, known as the branchpoint region, plays a central role in this process. We here describe a point mutation in such a sequence. Three sisters were shown to suffer from fish-eye disease (FED), a disorder which is caused by mutations in the gene coding for lecithin:cholesterol acyltransferase (LCAT). Sequencing of the LCAT gene of all three probands revealed compound heterozygosity for a missense mutation in exon 4 which is reported to underlie the FED phenotype, and a point mutation located in intron 4 (IVS4:T-22C). By performing in vitro expression of LCAT minigenes and reverse transcriptase PCR on mRNA isolated from leukocytes of the patient, this gene defect was shown to cause a null allele as the result of complete intron retention. In conclusion, we demonstrated that a point mutation in a lariat branchpoint consensus sequence causes a null allele in a patient with FED. In addition, our finding illustrates the importance of this sequence for normal human mRNA processing. Finally, this report provides a widely applicable strategy which ensures fast and effective screening for intronic defects that underlie differential gene expression.

show abstract

Section: Discussionmentioning

confidence: 99%

An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease).

Kuivenhoven¹,

Weibusch²,

Pritchard³

et al. 1996

J. Clin. Invest.

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show abstract

“…Otherwise, the bacterial enzyme was found in the soluble fraction, suggesting that ferrochelatase may exist originally as a soluble form. (Nakahashi et al 1990b;Nakahashi et al 1992). The two bands of human ferrochelatase mRNA are attributed to two polyadenylation sites (Nakahashi et al 1990b).…”

Section: Location Of Ferrochelatase In Mitochondriamentioning

confidence: 99%

Molecular and Genetic Characterization of Ferrochelatase.

Taketani

1993

Tohoku J. Exp. Med.

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“…The second mutation was a G to A at nucleotide 801, changing methionine to isoleucine at amino acid residue 267. The EPP patient, a young Caucasian girl, was subsequently analyzed for ferrochelatase activity [71]. The patient showed half the ferrochelatase activity and the protein found i n control subjects, as determined by immunoblot analysis.…”

Section: Molecular Basis Of Erythropoietic Protoporphyriamentioning

confidence: 99%

Molecular and genetic characterization of ferrochelatase

Taketani

1994

Stem Cells

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Abstract. Ferrochelatase (heme synthase, protoheme ferrolyase [EC 4.99.1.1]), the final enzyme of the heme biosynthetic pathway, catalyzes the insertion of ferrous ion into protoporphyrin IX to produce protoheme IX. The thorough understanding of the enzyme is prerequisite to elucidating the regulation of iron and heme metabolism. The enzyme's activity is found on the inner mitochondria1 membrane of a variety of mammalian cells. The enzyme catalyzes the chelation not only of iron but also of divalent metal ions including cobalt and zinc, and the activity is affected by various metals and lipids. The molecular weights of eukaryotic ferrochelatases are 40,000-42,000 daltons. Complementary DNA (cDNA) encoding ferrochelatase from mouse, human, yeast and bacteria have been isolated, and the derived amino acid sequences show 27438% homologies among species. The expression of ferrochelatase seems to occur in all living cells, and to play an important role in the regulation of heme biosynthesis. Ferrochelatase is markedly induced at the transcriptional level during erythroid differentiation when iron uptake by cells and hemoglobin synthesis are upregulated. This induction can be explained by the existence of sequences characteristic of erythroid-related genes. The gene has been mapped to human chromosome 18q21.3 and contains 11 exons with a size of about 45 kilobases. Once the gene for human ferrochelatase is cloned, the molecular basis and clinical diagnosis of erythropoietic protoporphyria, caused by a deficiency of ferrochelatase, will become possible. This review summarizes recent advances in ferrochelatase research and suggests important subjects for future research.

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

Cited by 76 publications

References 32 publications

An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease).

An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease).

Molecular and Genetic Characterization of Ferrochelatase.

Molecular and genetic characterization of ferrochelatase

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