The porphyrias: pathophysiology

Pietrangelo, Antonello

doi:10.1007/s11739-010-0452-z

Cited by 13 publications

(7 citation statements)

References 23 publications

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“…They are categorized in terms of the main tissue where the enzyme deficiency is expressed or by the clinical symptoms. Specific patterns of accumulation of the heme precursors d-aminolevulinic acid (ALA), porphobilinogen (PBG), and porphyrins are associated with characteristic clinical features such as acute neurovisceral attacks, skin lesions, or both (Pietrangelo 2010;Puy et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Variegate Porphyria Mutations Using a Minigene Approach

et al. 2014

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Porphyrias are a group of metabolic diseases that affect the skin and/or nervous system. In 2008, three unrelated patients were diagnosed with variegate porphyria at the CIPYP (Centro de Investigaciones sobre Porfirinas y Porfirias). Sequencing of the protoporphyrinogen oxidase gene, the gene altered in this type of porphyria, revealed three previously undescribed mutations: c.338+3insT, c.807G>A, and c.808-1G>C. As these mutations do not affect the protein sequence, we hypothesized that they might be splicing mutations. RT-PCRs performed on the patient's mRNAs showed normal mRNA or no amplification at all. This result indicated that the aberrant spliced transcript is possibly being degraded. In order to establish whether they were responsible or not for the patient's disease by causing aberrant splicing, we utilized a minigene approach. We found that the three mutations lead to exon skipping; therefore, the abnormal mRNAs are most likely degraded by a mechanism such as nonsense-mediated decay. In conclusion, these mutations are responsible for the disease because they alter the normal splicing pathway, thus providing a functional explanation for the appearance of disease and highlighting the use of minigene assays to complement transcript analysis.

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Section: Introductionmentioning

confidence: 99%

Characterization of Variegate Porphyria Mutations Using a Minigene Approach

et al. 2014

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“…Most enzyme defects represent partial deficiency, because a complete enzyme deficiency along the heme pathway is not compatible with life. 36 Heme synthesis starts in the mitochondria; the subsequent steps, from deamination, tetrapyrrole ring formation, to successive decarboxylation to 4-carboxyl porphyrinogen (coproporphyrinogen) take place in the cytoplasm. The final stages occur in the mitochondria (Fig 6).…”

Section: Drug-and Chemical-induced Photosensitivitymentioning

confidence: 99%

“…The human UROS gene has been assigned to the chromosome region 10q25.3 to q26.3. 36 Mutations in affected individuals are heterogenous. These include missense and nonsense mutations, large and small deletions and insertions, splicing defect, and intronic branch mutations.…”

Section: Congenital Erythropoietic Porphyriamentioning

confidence: 99%

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Photosensitivity disorders in children

Chantorn

Lim

Shwayder

2012

Journal of the American Academy of Dermatology

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“…1). Severe inhibition of human PBGS ( Hs PBGS) in vivo , which can occur through varied mechanisms discussed below, plays a role in multiple disease states [1-4]. The most common disease related to Hs PBGS inhibition is lead poisoning, which occurs via classic active-site inhibition [5].…”

Section: Introductionmentioning

confidence: 99%

Environmental Contaminants Perturb Fragile Protein Assemblies and Inhibit Normal Protein Function

Lawrence¹,

Selwood²,

Jaffe³

2013

CCB

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The molecular mechanisms whereby small molecules that contaminate our environment cause physiological effects are largely unknown, in terms of both targets and mechanisms. The essential human enzyme porphobilinogen synthase (HsPBGS, a.k.a. 5-aminolevulinate dehydratase, ALAD) functions in heme biosynthesis. HsPBGS catalytic activity is regulated allosterically via an equilibrium of inactive hexamers and active octamers, and we have shown that certain drugs and drug-like small molecules can inhibit HsPBGS in vitro by stabilizing the hexamer. Here we address whether components of the National Toxicology Program library of environmental contaminants can stabilize the HsPBGS hexamer and inhibit activity in vitro. Native polyacrylamide gel electrophoresis was used to screen the library (1,408 compounds) for components that alter the oligomeric distribution of HsPBGS. Freshly purchased samples of 37 preliminary hits were used to confirm the electrophoretic results and to determine the dose-dependence of the perturbation of oligomeric distribution. Seventeen compounds were identified which alter the oligomeric distribution toward the hexamer and also inhibit HsPBGS catalytic activity, including the most potent HsPBGS inhibitor yet characterized (Mutagen X, IC50 = 1.4 μM). PBGS dysfunction is associated with the inborn error of metabolism know as ALAD porphyria and with lead poisoning. The identified hexamer-stabilizing inhibitors could potentiate these diseases. Allosteric regulation of activity via an equilibrium of alternate oligomers has been proposed for many proteins. Based on the precedent set herein, perturbation of these oligomeric equilibria by small molecules (such as environmental contaminants) can be considered as a mechanism of toxicity.

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The porphyrias: pathophysiology

Cited by 13 publications

References 23 publications

Characterization of Variegate Porphyria Mutations Using a Minigene Approach

Characterization of Variegate Porphyria Mutations Using a Minigene Approach

Photosensitivity disorders in children

Environmental Contaminants Perturb Fragile Protein Assemblies and Inhibit Normal Protein Function

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