Seven novel point mutations in the uroporphyrinogen decarboxylase (UROD) gene in patients with familial porphyria cutanea tarda (f-PCT)

Cappellini, Maria Domenica; Montemuros, Franco Martinez di; Tavazzi, Dario; Pizzuti, Antonio; Comino, A.; Cainelli, T.; Fiorelli, G.

doi:10.1002/humu.35

Cited by 15 publications

(11 citation statements)

References 19 publications

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“…This center was established in 1974 and currently includes 239 index cases of porphyria, 101 of them being diagnosed with PCT (42.2%). In sum, our data strongly indicate that among Chilean PCT patients, the familial variant is more frequently encountered than in any other country in which molecular genetic studies in PCT families have been performed to date (20,23,24,26,27). The future inclusion and investigation of further Chilean individuals suffering from PCT will allow to estimate the ratio between familial and sporadic PCT more accurately.…”

Section: Barrel Of the Uro-d Proteinmentioning

confidence: 58%

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The molecular basis of porphyria cutanea tarda in Chile: Identification and functional characterization of mutations in the uroporphyrinogen decarboxylase gene

Poblete‐Gutiérrez

Méndez

Wiederholt

et al. 2004

Experimental Dermatology

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The porphyrias are heterogeneous disorders arising from predominantly inherited catalytic deficiencies of specific enzymes in heme biosynthesis. Porphyria cutanea tarda (PCT) results from a decreased activity of uroporphyrinogen decarboxylase, the fifth enzyme in heme biosynthesis. The disorder represents the only porphyria that is not exclusively inherited monogenetically. In PCT, at least two different types can be distinguished: acquired/sporadic (type I) PCT, in which the enzymatic deficiency is limited to the liver and inherited/familial (type II) PCT, which is inherited as an autosomal dominant trait with a decrease of enzymatic activity in all tissues. In an effort to characterize the molecular basis of PCT in Chile, we identified eight mutations in 18 previously unclassified PCT families by polymerase chain reaction, heteroduplex analysis, and automated sequencing. To study the role of these mutations in disease causality, in vitro expression of all novel missense mutations was studied. Our results indicate that the frequency of familial PCT in Chile is approximately 50%, thus, to our knowledge, representing the highest incidence of familial PCT reported to date. The data further emphasize the molecular heterogeneity in type II PCT and demonstrate the advantages of molecular genetic techniques as a diagnostic tool and in the detection of clinically asymptomatic mutation carriers.

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Section: Barrel Of the Uro-d Proteinmentioning

confidence: 58%

“…In heterozygotes suffering from type II PCT, URO-D activity is decreased by approximately 50% in all cells. The human URO-D cDNA and gene were previously cloned and mapped to chromosome 1p34 (15)(16)(17), and different groups have reported mutations in the URO-D gene in families with type II PCT (18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

The molecular basis of porphyria cutanea tarda in Chile: Identification and functional characterization of mutations in the uroporphyrinogen decarboxylase gene

Poblete‐Gutiérrez

Méndez

Wiederholt

et al. 2004

Experimental Dermatology

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“…Some PCT patients with 'familial' disease (*20%) have an inherited (autosomal dominant) deficiency of UROD due to mutations in the structural gene for this enzyme (type II) [19]. These individuals have an approximately 50% deficiency of UROD in all tissues and may develop PCT more readily than type I PCT subjects.…”

Section: Porphyria Cutanea Tarda and Hepatoerythropoietic Porphyriamentioning

confidence: 98%

The porphyrias: pathophysiology

Pietrangelo¹

2010

Intern Emerg Med

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Porphyrias are a group of inherited and acquired metabolic disorders due to a defect in haem biosynthesis. An enzymatic defect at different steps of haem synthesis leads to tissue accumulation and excessive excretion of porphyrins and/or their toxic precursors. The specific patterns of accumulation determine the variety of clinical manifestations, ranging from acute neurovisceral attacks to skin lesions and liver disease. Most enzyme defects represent partial deficiencies, while familial cases are linked to autosomal or recessive traits. The incomplete penetrance of the genetic defects often requires the triggering or aggravating effect of host-related or environmental factors. While genetics has a role in confirming clinical suspicion and in family screening, biochemical and clinical studies are still central in the diagnosis.

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“…Previously uncharacterized missense mutations were cloned into an expression system and purified for additional analysis. The P150L mutation that had been initially found in Italy but not expressed in prokaryotes was incorporated into this analysis (19). Recombinant UROD proteins were recovered from four of the mutants: A22V, F84I, T141I and Y182C ( Fig.…”

Section: Expression Of New Missense Mutations In Prokaryotesmentioning

confidence: 99%

Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives

et al. 2009

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Porphyria cutanea tarda (PCT) arises from decreased hepatic activity of uroporphyrinogen decarboxylase (UROD). Both genetic and environmental factors interplay in the precipitation of clinically overt PCT, but these factors may vary between different geographic areas. Decreased activity of UROD in erythrocytes was used to identify patients with UROD mutations among a group of 130 Spanish PCT patients. Nineteen patients (14.6%) were found to harbor a mutation in the UROD gene. Eight mutations were novel: M1I, 5del10, A22V, D79N, F84I, Q116X, T141I and Y182C. Five others were previously described: F46L, V134Q, R142Q, P150L and E218G. The new missense mutations and P150L were expressed in Escherichia coli. D79N and P150L resulted in proteins that were localized to inclusion bodies. The other mutations produced recombinant proteins that were purified and showed reduced activity (range: 2.3–73.2% of wild type). These single amino acid changes were predicted to produce complex structural alterations and/or reduced stability of the enzyme. Screening of relatives of the probands showed that 37.5% of mutation carriers demonstrated increased urinary porphyrins. This study emphasizes the role of UROD mutations as a strong risk factor for PCT even in areas where environmental factors (hepatitis C virus) have been shown to be highly associated with the disease.

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Seven novel point mutations in the uroporphyrinogen decarboxylase (UROD) gene in patients with familial porphyria cutanea tarda (f-PCT)

Cited by 15 publications

References 19 publications

The molecular basis of porphyria cutanea tarda in Chile: Identification and functional characterization of mutations in the uroporphyrinogen decarboxylase gene

The molecular basis of porphyria cutanea tarda in Chile: Identification and functional characterization of mutations in the uroporphyrinogen decarboxylase gene

The porphyrias: pathophysiology

Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives

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