Erythropoietic porphyria
Encyclopedia
Erythropoietic porphyria is a type of porphyria
associated with erythropoietic cells. In erythropoietic porphyrias, the enzyme deficiency occurs in the red blood cell
s.
There are three types:
X-linked sideroblastic anemia or "X-linked dominant erythropoietic protoporphyria", associated with ALAS2
(aminolevulinic acid synthase
), has also been described. X-linked dominant erythropoietic protoporphyria (XDEPP) is caused be a gain of function mutation in the ALAS2 (5-aminolevulinate synthase) gene; the very first enzyme in the Heme biosynthetic pathway. The mutation is caused by a frameshift mutation caused by one of two deletions in the ALAS2 exon 11, either c. 1706-1709 delAGTG or c. 1699-1700 delAT. This alters the 19th and 20th residues of the C-terminal domain thereby altering the 2° structure of the enzyme. The delAT mutation only occurred in one family studied whereas the delAGTG mutation occurred in several genetically distinct families. The delAGTG causes a loss of an a-helix which is replaced by a ß-sheet.
Previously known mutations in the ALAS2 resulted in a loss-of-function mutation causing X-linked sideroblastic anemia. Erythropoietic protoporphyria (EPP) has similar symptoms as X-linked dominant erythropoietic protoporphyria but the mutation occurs as a loss-of-function in the FECH (ferrochelatase ) enzyme; the very last enzyme in the pathway. All individuals studied presented symptoms without mutations in the FECH enzyme. The patterns of inheritance led the researchers to conclude the mutation must come from an enzyme on the X-chromosome with ALAS2 being the most likely candidate.
X-linked dominant erythropoietic protoporphyria is distinct from EPP in that there is no overload of Fe2+ ions. Additionally, unlike the other the other condition the arises out of a mutation of the ALAS2 gene, there is no anemia. XDEPP is characterized by a build up of Protoporphyrin IX caused by in increased level of function in the ALAS2 enzyme. Because there is a build up of Proporphyrin IX with no malfunction of the FECH enzyme, all the available Fe2+ is used in the production of Heme causing the FECH enzyme to use Zn2+ in its place causing a build up of Zinc Protoporphyrin IX.
X-linked dominant erythropoietic protoporphyria is a relatively mild version of porphyria with the predominate symptom being extreme photo sensitivity causing severe itching and burning of the skin due to the buildup of Protoporphyrin IX. One possible treatment was discovered when treating an individual with supplemental Iron for a gastric ulcer. Levels of free Protoporphyrin decreased significantly as there was iron available for the FECH to produce Heme. Levels of Zn Protoporphyrin, however did not decrease.
Porphyria
Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...
associated with erythropoietic cells. In erythropoietic porphyrias, the enzyme deficiency occurs in the red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s.
There are three types:
| Name | OMIM | Gene |
|---|---|---|
| erythropoietic protoporphyria Erythropoietic protoporphyria Erythropoietic protoporphyria is a relatively mild form of porphyria, although very painful, which arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the tissue... (EPP) |
ferrochelatase Ferrochelatase Ferrochelatase is an enzyme that catalyses the terminal step in the biosynthesis of heme, converting protoporphyrin IX into heme. It catalyses the reaction:A ferrochelatase enzyme consists of 497 amino acid residues with a m.w... |
|
| congenital erythropoietic porphyria or "Gunther's" (CEP) | uroporphyrinogen III synthase Uroporphyrinogen III synthase Uroporphyrinogen III synthase is an enzyme involved in the metabolism of the cyclic tetrapyrrole compound porphyrin. It is involved in the conversion of hydroxymethyl bilane into uroporphyrinogen III... |
|
| hepatoerythropoietic porphyria Hepatoerythropoietic porphyria Hepatoerythropoietic porphyria is a very rare form of hepatic porphyria caused by a disorder in both genes which code Uroporphyrinogen III decarboxylase .It has a similar presentation to porphyria cutanea tarda , but with earlier onset... |
uroporphyrinogen III decarboxylase Uroporphyrinogen III decarboxylase Uroporphyrinogen decarboxylase, also known as UROD, is an enzyme that in humans is encoded by the UROD gene.- Function :This gene encodes the fifth enzyme of the heme biosynthetic pathway... |
X-linked sideroblastic anemia or "X-linked dominant erythropoietic protoporphyria", associated with ALAS2
ALAS2
Delta-aminolevulinate synthase 2 also known as ALAS2 is a protein that in humans is encoded by the ALAS2 gene. ALAS2 is an aminolevulinic acid synthase....
(aminolevulinic acid synthase
Aminolevulinic acid synthase
ALA synthase catalyzes the synthesis of D-Aminolevulinic acid the first common precursor in the biosynthesis of all tetrapyrroles. The enzyme is expressed in all non-plant eukaryotes and the α-class of proteobacteria. Other organisms produce ALA through a three enzyme pathway known as the Shemin...
), has also been described. X-linked dominant erythropoietic protoporphyria (XDEPP) is caused be a gain of function mutation in the ALAS2 (5-aminolevulinate synthase) gene; the very first enzyme in the Heme biosynthetic pathway. The mutation is caused by a frameshift mutation caused by one of two deletions in the ALAS2 exon 11, either c. 1706-1709 delAGTG or c. 1699-1700 delAT. This alters the 19th and 20th residues of the C-terminal domain thereby altering the 2° structure of the enzyme. The delAT mutation only occurred in one family studied whereas the delAGTG mutation occurred in several genetically distinct families. The delAGTG causes a loss of an a-helix which is replaced by a ß-sheet.
Previously known mutations in the ALAS2 resulted in a loss-of-function mutation causing X-linked sideroblastic anemia. Erythropoietic protoporphyria (EPP) has similar symptoms as X-linked dominant erythropoietic protoporphyria but the mutation occurs as a loss-of-function in the FECH (ferrochelatase ) enzyme; the very last enzyme in the pathway. All individuals studied presented symptoms without mutations in the FECH enzyme. The patterns of inheritance led the researchers to conclude the mutation must come from an enzyme on the X-chromosome with ALAS2 being the most likely candidate.
X-linked dominant erythropoietic protoporphyria is distinct from EPP in that there is no overload of Fe2+ ions. Additionally, unlike the other the other condition the arises out of a mutation of the ALAS2 gene, there is no anemia. XDEPP is characterized by a build up of Protoporphyrin IX caused by in increased level of function in the ALAS2 enzyme. Because there is a build up of Proporphyrin IX with no malfunction of the FECH enzyme, all the available Fe2+ is used in the production of Heme causing the FECH enzyme to use Zn2+ in its place causing a build up of Zinc Protoporphyrin IX.
X-linked dominant erythropoietic protoporphyria is a relatively mild version of porphyria with the predominate symptom being extreme photo sensitivity causing severe itching and burning of the skin due to the buildup of Protoporphyrin IX. One possible treatment was discovered when treating an individual with supplemental Iron for a gastric ulcer. Levels of free Protoporphyrin decreased significantly as there was iron available for the FECH to produce Heme. Levels of Zn Protoporphyrin, however did not decrease.