The molecular defect of ferrochelatase in a patient with erythropoietic protoporphyria
Yoshitsugu Nakahashi,Hiroyoshi Fujita,Shigeru Taketani,Nobuhiro Ishida,Attallah Kappas,Shigeru Sassa +5 more
TLDR
In Epstein-Barr 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, suggesting that decreased ferroChelatase mRNA is due to an unstable transcript.Abstract:
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 Epstein-Barr 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 transcription 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 classified 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.read more
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Ferrochelatase at the millennium: structures, mechanisms and [2Fe-2S] clusters
TL;DR: DNA sequences along with direct protein studies reveal that ferrochelatases, while related, vary significantly in amino acid sequence, molecular size, subunit composition, solubility, and the presence or absence of nitric-oxide-sensitive [2Fe-2S] cluster.
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Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families : A nationwide study of Btk deficiency in Japan
Shoji Hashimoto,Satoshi Tsukada,Masato Matsushita,Toshio Miyawaki,Yo Niida,Akihiro Yachie,Shigetoshi Kobayashi,Tsutomu Iwata,Hiroshi Hayakawa,Hiroshi Matsuoka,Ikuya Tsuge,Tomoki Yamadori,Toshio Kunikata,Shigeyuki Arai,Kazuyuki Yoshizaki,Noboru Taniguchi,Tadamitsu Kishimoto +16 more
TL;DR: A nationwide study of Btk deficiency in Japan, covering 51 XLA patients (35 independent families), identified several novel missense mutations and clarified the presence of two (missense) mutation hot spots in the SH1 and the PH domain.
Journal ArticleDOI
Inheritance in Erythropoietic Protoporphyria: A Common Wild-Type Ferrochelatase Allelic Variant With Low Expression Accounts for Clinical Manifestation
Laurent Gouya,Hervé Puy,Jérôme Lamoril,Vasco Da Silva,Bernard Grandchamp,Yves Nordmann,Jean-Charles Deybach +6 more
TL;DR: It is shown that coinheritance of a FECH gene defect and a wild-type low-expressed allele is generally involved in the clinical expression of EPP, and that EPP may represent a model for phenotype modulation by mild variation in expression of the wild- type allele in autosomal dominant diseases.
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Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele.
Laurent Gouya,Jean Charles Deybach,Jérôme Lamoril,V. Da Silva,Carole Beaumont,Bernard Grandchamp,Yves Nordmann +6 more
TL;DR: The data support the hypothesis that in this EPP phenotype results from the coinheritance of a low output normal FC allele and a mutant delta Ex10 allele, suggesting a more complex mode of inheritance.
Journal ArticleDOI
An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease).
Jan Albert Kuivenhoven,H Weibusch,P.H. Pritchard,H. Funke,R Benne,G. Assmann,J.J.P. Kastelein +6 more
TL;DR: It is demonstrated that a point mutation in a lariat branchpoint consensus sequence causes a null allele in a patient with FED, a widely applicable strategy which ensures fast and effective screening for intronic defects that underlie differential gene expression.