A point mutation affecting an SP1 binding site in the promoter of the ferrochelatase gene impairs gene transcription and causes erythropoietic protoporphyria

Pierro, Elena Di; Cappellini, Maria Domenica; Mazzucchelli, Renata; Moriondo, Valeria; Mologni, Daniela; Poma, Barbara Zanone; Riva, Agostino

doi:10.1016/j.exphem.2005.02.001

Cited by 20 publications

(20 citation statements)

References 26 publications

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“…Mutations and polymorphisms at the Sp1/Sp3 binding sites in promoter regions were reported to be related to several diseases [18,19,20,21,22,23]. Our data in HEK 293 cells here showed that point mutation at the Sp1/Sp3-A, -B, -C or -D site alone did not lead to significant change of the promoter activity.…”

Section: Discussionsupporting

confidence: 57%

Functional Characterization of the Regulatory Region of Human CD2-Associated Protein Promoter in HEK 293 Cells

Ren

Lü

et al. 2008

Am J Nephrol

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Background: The mRNA of CD2-associated protein (CD2AP) was found to be changed in glomerular diseases. The promoter plays an important role in the regulation of gene expression, but the characterization of the human CD2AP promoter has not been systematically analyzed in HEK 293 cells. Aims: To analyze in detail the promoter of human CD2AP in HEK 293 cells. Methods: The transcriptional initiation sites were identified by 5′ RACE. Promoter activities were detected by series deletion and mutational luciferase analyses. Results: Multiple transcriptional start sites were identified. Progressive deletion analysis from both 5′ and 3′ ends revealed two kinds of promoter activity. One basic promoter activity was located within 500 bp upstream of ATG. Fragments of further upstream 100 bp increased the promoter activity 5-fold. Two Sp1/Sp3 sites were in this region. Mutations of these two sites reduced the transcriptional activity by 50%. Sp1 increased the activity, whereas Sp3 decreased the activity. Deletion of 9 single nucleotide polymorphism sites and 3 Lmx1b sites did not change the transcriptional activity.Conclusion: Sp1/Sp3 binding sites play a critical role in the CD2AP regulation. These findings should facilitate studies on the clinical mutational and polymorphism analysis.

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Section: Discussionsupporting

confidence: 57%

Functional Characterization of the Regulatory Region of Human CD2-Associated Protein Promoter in HEK 293 Cells

Ren

Lü

et al. 2008

Am J Nephrol

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“…FECH catalyzes the insertion of iron into protoporphyrin IX to form protoheme. The molecular cloning and sequence analysis of human FECH cDNA was reported in 1990; 2 subsequently, as many as 90 different mutations affecting the coding regions or splicing junctions have been identified in EPP patients 3 . Our search of the English‐language published work found six Japanese EPP patients in whom genetic analysis of the FECH gene was performed; 4–9 another four patients were reported in the Japanese published work or in conference abstracts.…”

Section: Introductionmentioning

confidence: 96%

Genetic analysis of the ferrochelatase gene in eight Japanese patients from seven families with erythropoietic protoporphyria

Saruwatari

Ueki

Yotsumoto

et al. 2006

The Journal of Dermatology

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A decrease in the activity of ferrochelatase (FECH; EC 4.99.1.1), the terminal enzyme of the heme biosynthetic pathway, results in erythropoietic protoporphyria (EPP; MIM 177000). We analyzed the FECHgene in eight Japanese EPP patients from seven non-consanguineous families and found two distinct genomic DNA abnormalities. In six patients from five families, there was a G-to-A point-mutation at the first position of the intron 9 donor site; it resulted in aberrant splicing and skipping of exon 9 in FECH mRNA. In one patient, we found an A-to-G point-mutation 4 bases from the 3" terminus of intron 4 that led to the in-frame insertion of 3 bases in mRNA. No allelic anomalies, except for 3 single nucleotide polymorphisms were detected in another patient. We analyzed intron polymorphism at IVS3-48, known to be associated with the phenotypic expression of EPP, in these eight patients and 152 healthy Japanese volunteers. All patients were C/C homozygous for IVS3-48. The allelic frequency of IVS3-48C polymorphism in the healthy Japanese volunteers was 67.8% (103/152).

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“…Studies conducted to identify the causes of the low expression of the wild type allele suggest the involvement of intragenic polymorphisms [57,58]. There are evidences indicating that an haplotype of three polymorphisms (-251G, IVS1-23T and IVS3-48C: GTC haplotype) in the promoter, intron 1 and intron 3, respectively, could be responsible for the reduced expression of the wild type allele [58,59]. Subjects carrying only a mutation result to be completely asymptomatic, showing fluorocytes percentage of 0.3-1.5%, while carriers of the GTC haplotype show fluorocytes values completely overlying to normal subjects (0-0.3%).…”

Section: Clinical Presentation and Diagnosis Of Chronic Porphyriasmentioning

confidence: 99%

Porphyrias at a glance: diagnosis and treatment

et al. 2010

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Porphyrias are a group of eight rare inherited metabolic disorders of heme biosynthesis pathway. Porphyrias are still underdiagnosed, although examinations of urine and plasma are first-line tests for detecting excess of porphyrins or heme precursors in suspected patients. Diagnosis, particularly for the acute forms, is essential to avoid precipitating factors and the use of triggering drugs. Mutation screening of family members is recommended to identify presymptomatic carriers and to prevent acute attacks. The therapeutic approach should be appropriate regarding specific forms of porphyria and treatment should be started promptly.

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A point mutation affecting an SP1 binding site in the promoter of the ferrochelatase gene impairs gene transcription and causes erythropoietic protoporphyria

Cited by 20 publications

References 26 publications

Functional Characterization of the Regulatory Region of Human CD2-Associated Protein Promoter in HEK 293 Cells

Functional Characterization of the Regulatory Region of Human CD2-Associated Protein Promoter in HEK 293 Cells

Genetic analysis of the ferrochelatase gene in eight Japanese patients from seven families with erythropoietic protoporphyria

Porphyrias at a glance: diagnosis and treatment

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