New Missense Mutation in the Human Ferrochelatase Gene in a Family with Erythropoietic Protoporphyria: Functional Studies and Correlation of Genotype and Phenotype

Rüfenacht, Urszula B.; Gregor, A; Gouya, Laurent; Tarczyńska-Nosal, S; Schneider‐Yin, Xiaoye; Deybach, Jean‐Charles

doi:10.1093/clinchem/47.6.1112

Cited by 5 publications

(3 citation statements)

References 5 publications

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“…Most of the missense mutations found in heterozygous EPP cases show a drastic reduction or even undetectable activity when expressed in prokaryotes. [27][28][29] In contrast, in a report of recessive EPP, all the mutations retained a FECH residual activity ranging from 12% to 50% when expressed in E coli. 12 This is in accordance with the general view that homozygous cases of porphyria must retain a substantial residual enzyme activity to be compatible with life.…”

Section: Commentmentioning

confidence: 71%

Clinical, Biochemical, and Genetic Study of 11 Patients With Erythropoietic Protoporphyria Including One With Homozygous Disease

Herrero

To‐Figueras²,

Badenas³

et al. 2007

Arch Dermatol

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To study the mutations in the ferrochelatase gene (FECH) and the phenotypic expression of erythropoietic protoporphyria (EPP) in a group of Spanish patients. Design: Case series. Setting: University-based hospital. Patients: Eleven unrelated patients with EPP and 19 asymptomatic relatives from 10 families. Main Outcomes Measures: Measurement of protoporphyrin concentration in red blood cells and feces by fluorometry and chromatography. Analysis of the mutations of the FECH gene by single-strand conformation analysis. Expression of mutations in Escherichia coli.Results: FECH gene mutations were found in all 11 patients. Ten were heterozygous and carried the IVS3-48C low-expression allele. Three novel mutations were found: IVS4ϩ 1delG, 347-351delC, and 130_147dupl 18. One

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Section: Commentmentioning

confidence: 71%

Clinical, Biochemical, and Genetic Study of 11 Patients With Erythropoietic Protoporphyria Including One With Homozygous Disease

Herrero

To‐Figueras²,

Badenas³

et al. 2007

Arch Dermatol

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“…Mutations that render FECH inactive cause erythropoietic protoporphyria and liver damage. 174 As discussed above, heme biosynthesis has been extensively studied, but the process by which heme is ferried across mitochondrial membranes into the cytosol for association with globins and apo cytochromes remains unknown. Likewise, no specific transporters or receptors that facilitate mitochondrial export of heme have been reported.…”

Section: •−mentioning

confidence: 99%

“…The final step, insertion of iron into protoporphyrin, is catalyzed by mitochondrial ferrochelatase (Fech). Mutations that render FECH inactive cause erythropoietic protoporphyria and liver damage . As discussed above, heme biosynthesis has been extensively studied, but the process by which heme is ferried across mitochondrial membranes into the cytosol for association with globins and apo cytochromes remains unknown.…”

Section: Cellular Iron Metabolismmentioning

confidence: 99%

Mechanisms of Mammalian Iron Homeostasis

Pantopoulos

Porwal²,

Tartakoff³

et al. 2012

Biochemistry

479

459

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Iron is vital for almost all organisms because of its ability to donate and accept electrons with relative ease. It serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism, as well as for several other essential processes. Mammalian cells utilize multiple mechanisms to acquire iron. Disruption of iron homeostasis is associated with various human diseases: iron deficiency resulting from defects in the acquisition or distribution of the metal causes anemia, whereas iron surfeit resulting from excessive iron absorption or defective utilization causes abnormal tissue iron deposition, leading to oxidative damage. Mammals utilize distinct mechanisms to regulate iron homeostasis at the systemic and cellular levels. These involve the hormone hepcidin and iron regulatory proteins, which collectively ensure iron balance. This review outlines recent advances in iron regulatory pathways as well as in mechanisms underlying intracellular iron trafficking, an important but less studied area of mammalian iron homeostasis.

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An X-chromosome linked mouse model ( Ndufa1 S55A ) for systemic partial Complex I deficiency for studying predisposition to neurodegeneration and other diseases

Kim

Potluri

Khalil

et al. 2017

Neurochemistry International

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The respiratory chain Complex I deficiencies are the most common cause of mitochondrial diseases. Complex I biogenesis is controlled by 58 genes and at least 47 of these cause mitochondrial disease in humans. Two of these are X-chromosome linked nuclear (nDNA) genes (NDUFA1 and NDUFB11), and 7 are mitochondrial (mtDNA, MT-ND1-6, -4L) genes, which may be responsible for sex-dependent variation in the presentation of mitochondrial diseases. In this study, we describe an X-chromosome linked mouse model (Ndufa1) for systemic partial Complex I deficiency. By homologous recombination, a point mutation T > G within 55th codon of the Ndufa1 gene was introduced. The resulting allele Ndufa1 introduced systemic serine-55-alanine (S55A) mutation within the MWFE protein, which is essential for Complex I assembly and stability. The S55A mutation caused systemic partial Complex I deficiency of ∼50% in both sexes. The mutant males (Ndufa1) displayed reduced respiratory exchange ratio (RER) and produced less body heat. They were also hypoactive and ate less. They showed age-dependent Purkinje neurons degeneration. Metabolic profiling of brain, liver and serum from males showed reduced heme levels in mutants, which correlated with altered expressions of Fech and Hmox1 mRNAs in tissues. This is the first genuine X-chromosome linked mouse model for systemic partial Complex I deficiency, which shows age-dependent neurodegeneration. The effect of Complex I deficiency on survival patterns of males vs. females was different. We believe this model will be very useful for studying sex-dependent predisposition to both spontaneous and stress-induced neurodegeneration, cancer, diabetes and other diseases.

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New Missense Mutation in the Human Ferrochelatase Gene in a Family with Erythropoietic Protoporphyria: Functional Studies and Correlation of Genotype and Phenotype

Cited by 5 publications

References 5 publications

Clinical, Biochemical, and Genetic Study of 11 Patients With Erythropoietic Protoporphyria Including One With Homozygous Disease

Clinical, Biochemical, and Genetic Study of 11 Patients With Erythropoietic Protoporphyria Including One With Homozygous Disease

Mechanisms of Mammalian Iron Homeostasis

An X-chromosome linked mouse model ( Ndufa1 S55A ) for systemic partial Complex I deficiency for studying predisposition to neurodegeneration and other diseases

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