Abstract
Both familial and sporadic porphyria cutanea tarda (PCT) are iron dependent diseases. Symptoms of PCT resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y, c.843G>A, rs1800562) that enhances iron aborption by reducing hepcidin expression is a risk factor for PCT. Recently, a polymorphic variant (D519G, c.1556A>G, rs11558492) of glyceronephosphate O-acyltransferase (GNPAT) was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype, suggesting that GNPAT D519G, like HFE C282Y, is a modifier of iron homeostasis that favors iron absorption. To challenge this hypothesis, we investigated the frequency of GNPAT D519G in patients with both familial and sporadic PCT. Patients were screened for GNPAT D519G and allelic variants of HFE (both C282Y and H63D). Nucleotide sequencing of uroporphyrinogen decarboxylase (URO-D) identified mutant alleles. Patients with low erythrocyte URO-D activity or a damaging URO-D variant were classified as familial PCT (fPCT) and those with wild-type URO-D were classified as sporadic PCT (sPCT). GNPAT D519G was significantly enriched in the fPCT patient population (p = 0.0014) but not in the sPCT population (p = 0.4477). Both HFE C282Y and H63D (c.187C>G, rs1799945) were enriched in both PCT patient populations (p<0.0001) but showed no greater association with fPCT than with sPCT. Conclusion: GNPAT D519G is a risk factor for fPCT, but not for sPCT.
Highlights
The cutaneous photosensitivity of porphyria cutanea tarda (PCT) results from abnormally low hepatic uroporphyrinogen decarboxylase (URO-D) activity. [1] Viewed stepwise, URO-D is the fifth of eight enzymes that participate in the heme biosynthetic pathway, and its function is to catalyze the conversion of uroporphyrinogen III to coproporphyrinogen III by the sequential removal from the tetrapyrrole of four carboxyl groups
Patients with low erythrocyte URO-D activity or a damaging URO-D variant were classified as familial PCT and those with wild-type URO-D were classified as sporadic PCT
Other factors including hepatitis C (HCV) infection, excess alcohol consumption, and therapeutic estrogens, in women,[4] increase the risk of developing PCT, but the importance of iron in the pathophysiology of the disease is underscored by the observation that symptoms resolve and plasma porphyrin levels return to normal when iron stores are depleted by therapeutic phlebotomy.[5, 6]
Summary
The cutaneous photosensitivity of PCT results from abnormally low hepatic URO-D activity. [1] Viewed stepwise, URO-D is the fifth of eight enzymes that participate in the heme biosynthetic pathway, and its function is to catalyze the conversion of uroporphyrinogen III to coproporphyrinogen III by the sequential removal from the tetrapyrrole of four carboxyl groups. The cutaneous photosensitivity of PCT results from abnormally low hepatic URO-D activity. The block in hepatic metabolism caused by URO-D deficiency leads to accumulation within the liver of byproducts of heme synthesis (porphyrins) that subsequently enter the plasma. PCT is unique because the majority of cases are not the result of inherited mutations of the defective enzyme. In cases in which there is a heterozygous mutation of URO-D (fPCT), the disease phenotype is observed only if the functional activity of the wild-type enzyme is inhibited. (In the homozygous or compound heterozygous state, mutant URO-D causes hepatoerythropoietic porphyria, a rare, clinically severe, congenital, cutaneous porphyria.) We have identified a porphomethene as the inhibitor of URO-D, and formation of the inhibitor is an iron dependent process.[3] other unidentified physiologically relevant URO-D inhibitors may exist. Other factors including hepatitis C (HCV) infection, excess alcohol consumption, and therapeutic estrogens, in women,[4] increase the risk of developing PCT, but the importance of iron in the pathophysiology of the disease is underscored by the observation that symptoms resolve and plasma porphyrin levels return to normal when iron stores are depleted by therapeutic phlebotomy.[5, 6] PCT is an iron-dependent disease and genetic variations of HFE (C282Y and H63D) that increase iron absorption by reducing expression of hepcidin are risk factors for developing PCT.[7,8,9]
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