ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria

To‐Figueras, Jordi; Ducamp, Sarah; Clayton, Jerome; Badenas, Cèlia; Delaby, Constance; Ged, Cécile; Lyoumi, Saı̈d; Gouya, Laurent; Verneuil, Hubert de; Beaumont, Carole; Ferreira, Glória C.; Deybach, Jean‐Charles; Herrero, Carmen; Puy, Hervé

doi:10.1182/blood-2011-03-342873

Cited by 81 publications

(67 citation statements)

References 38 publications

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“…Cellular heme synthesis was assayed by 55 Fe-heme incorporation. Consistent with previous data, 55 Fe-heme incorporation confirmed that Fe-dextran with DP, comprised mutations in multiple components of the heme synthetic pathway (43,44). Of note, mutations in Mfrn1 (also known as Slc25a37), required for mitochondrial iron import (28), do not by themselves cause porphyria (27).…”

Section: Tmem14c Expression Is Enriched In Mammalian Erythropoietic Tsupporting

confidence: 87%

TMEM14C is required for erythroid mitochondrial heme metabolism

Yien¹,

Robledo²,

Schultz³

et al. 2014

J. Clin. Invest.

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Section: Tmem14c Expression Is Enriched In Mammalian Erythropoietic Tsupporting

confidence: 87%

TMEM14C is required for erythroid mitochondrial heme metabolism

Yien¹,

Robledo²,

Schultz³

et al. 2014

J. Clin. Invest.

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“…Ferrochelatase activity is normal in these cells but they contain elevated levels of PPIX due to a gain-of-function mutation in the gene encoding ALAS2. The mutant enzyme upregulates the entry of succinyl-CoA and glycine precursors into the heme biosynthesis pathway, 29 resulting in substrate build up at the next ratelimiting step, which is ferrochelatase. 30,31 Individuals with XLDPP are clinically identical to EPP patients and their red cells contain similarly elevated levels of PPIX and are morphologically and physiologically very similar; ferrochelatase activity is, however, normal (supplemental Table 1).…”

Section: Resultsmentioning

confidence: 99%

Red cells from ferrochelatase-deficient erythropoietic protoporphyria patients are resistant to growth of malarial parasites

Smith

Jerkovic

Puy

et al. 2015

Blood

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Key Points• Malarial parasite growth is impeded in erythropoietic protoporphyric erythrocytes because of decreased host cell ferrochelatase activity.• A ferrochelatase competitive inhibitor prevents the growth of malarial parasites in normal red cells.Many red cell polymorphisms are a result of selective pressure by the malarial parasite.Here, we add another red cell disease to the panoply of erythrocytic changes that give rise to resistance to malaria. Erythrocytes from individuals with erythropoietic protoporphyria (EPP) have low levels of the final enzyme in the heme biosynthetic pathway, ferrochelatase. Cells from these patients are resistant to the growth of Plasmodium falciparum malarial parasites. This phenomenon is due to the absence of ferrochelatase and not an accumulation of substrate, as demonstrated by the normal growth of P falciparum parasites in the EPP phenocopy, X-linked dominant protoporphyria, which has elevated substrate, and normal ferrochelatase levels. This observation was replicated in a mouse strain with a hypomorphic mutation in the murine ferrochelatase gene. The parasite enzyme is not essential for parasite growth as Plasmodium berghei parasites carrying a complete deletion of the ferrochelatase gene grow normally in erythrocytes, which confirms previous studies. That ferrochelatase is essential to parasite growth was confirmed by showing that inhibition of ferrochelatase using the specific competitive inhibitor, N-methylprotoporphyrin, produced a potent growth inhibition effect against cultures of P falciparum. This raises the possibility of targeting human ferrochelatase in a host-directed antimalarial strategy. (Blood. 2015;125(3):534-541)

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“…32 More recently, a severely affected CEP patient with 2 UROS mutations was found to have a gain-of-function mutation in the ALAS2 gene, which increased disease severity compared with affected siblings who did not have the ALAS2 mutation. 33 …”

Section: Diagnosismentioning

confidence: 99%

The porphyrias: advances in diagnosis and treatment

Balwani

Desnick

2012

Blood

218

240

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The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous," and "erythropoietic cutaneous" diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overloadinduced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroidspecific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic prophyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders. (Blood. 2012;120(23):4496-4504)

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ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria

Cited by 81 publications

References 38 publications

TMEM14C is required for erythroid mitochondrial heme metabolism

TMEM14C is required for erythroid mitochondrial heme metabolism

Red cells from ferrochelatase-deficient erythropoietic protoporphyria patients are resistant to growth of malarial parasites

The porphyrias: advances in diagnosis and treatment

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