Disease relevance of UROD

• All mutations were observed in conjunction with decreased erythrocyte UROD and clinical familial porphyria cutanea tarda (fPCT), (four families) or hepatoerythropoietic porphyria (HEP), (one family) [1].
• In contrast to the null activity previously described for a mutant UROD from a patient with familial porphyria cutanea tarda, these mutant URODs had subnormal but substantial enzyme activities, when expressed in Chinese hamster ovary cells [2].
• Mild to moderate iron overload is common in PCT, as iron is one of the factors which trigger the clinical manifestations of the disease through the inactivation of URO-D [3].
• In PCT patients with liver disease, the presence of the mutation could contribute to the inactivation of URO-D, either directly or through a synergistic action with other factors that cause liver damage [3].
• Porphyria cutanea tarda (PCT), a disorder characterized by a photosensitive dermatosis and hepatic siderosis, is caused by a decreased activity of the hepatic enzyme uroporphyrinogen decarboxylase (UROD) [4].

Psychiatry related information on UROD

• The UPD group, although impaired on a spatial recognition task, showed intact discrimination learning and reversal; the MPD and SPD patients showed non-perseverative reversal impairments on both reversal tasks [5].
• More visuospatial deficits tend to be found in BPD and UPD than in schizophrenia, thereby raising the possibility of greater involvement of right hemisphere systems in mood disorders [6].
• Porphyria cutanea tarda, which is due to a deficiency of uroporphyrinogen decarboxylase, is manifested in association with alcohol abuse, estrogen therapy, exposure to chlorinated hydrocarbons or increased tissue iron stores, or a combination of these factors [7].
• Chronic alcohol consumption in rats leads to a decrease in uroporphyrinogen decarboxylase activity in liver and spleen, associated with a pathologic porphyrinuria [8].
• RESULTS: UPD cases exhibited significantly more autistic-like impairments in reciprocal social interaction on questionnaire, interview and standardised observational measures [9].

High impact information on UROD

• Ectopic expression of either UPD or JAK is sufficient to induce extra epithelial cells to migrate [10].
• Hepatoerythropoietic porphyria is caused by a marked deficiency in the activity of uroporphyrinogen decarboxylase, an enzyme that is essential for heme biosynthesis [11].
• Decreased hepatic uroporphyrinogen decarboxylase activity in porphyria cutanea tarda [12].
• To investigate the role of uroporphyrinogen decarboxylase in the pathogenesis of the sporadic form of porphyria cutanea tarda, we measured this enzyme in liver, erythrocytes and cultured skin fibroblasts, and also measured coproporphyrinogen oxidase and the total iron concentration in liver [13].
• The mean uroporphyrinogen decarboxylase activity was lower in liver from seven male patients (9.0 pmol of coproporphyrin per minute per milligram of protein) than in 12 controls, including seven with alcoholic liver disease (22.3 pmol per minute per milligram; P less than 0.05) [13].

Chemical compound and disease context of UROD

• At least 30 different mutations of the UROD gene have been identified in patients with HEP and familial porphyria cutanea tarda, with 1 predominant missense mutation (glycine-to-glutamic acid substitution at codon 281) in Spanish patients with HEP [14].
• As in the human syndrome porphyria cutanea tarda, iron administration increased porphyrin accumulation and the degree of reduction of UROD activity in mice fed HCB [15].
• Porphyria cutanea tarda (PCT) is a metabolic disorder of heme biosynthesis, characterized by reduced uroporphyrinogen decarboxylase (UROD) activity and increased urinary excretion of eight and seven carboxyl group porphyrins [16].
• Dual mechanism of inhibition of rat liver uroporphyrinogen decarboxylase activity by ferrous iron: its potential role in the genesis of porphyria cutanea tarda [17].
• Effects of polychlorinated biphenyl compounds, 2,3,7,8-tetrachlorodibenzo-p-dioxin, phenobarbital and iron on hepatic uroporphyrinogen decarboxylase. Implications for the pathogenesis of porphyria [18].

Biological context of UROD

• The six novel UROD mutations comprise three missense mutations (M01T, F229L, and M324T), two splice mutations (IVS3-2A-->T and IVS5-2A-->G) leading to exon skipping, and a 2-bp deletion (415-416delTA) resulting in a frameshift and the introduction of a premature stop codon [19].
• UROD phenotype studies demonstrated that the TGT-->CCA mutation was inherited from the father, and the A-->C mutation was inherited from the mother [2].
• Our data confirm that homozygosity for the F46L mutation in the UROD gene causes a mild form of HEP and show that this genotype may be associated with a unique urinary porphyrin excretion pattern in which pentacarboxylic porphyrin predominates [20].
• Seven novel point mutations in the uroporphyrinogen decarboxylase (UROD) gene in patients with familial porphyria cutanea tarda (f-PCT) [21].
• Dual porphyria in double heterozygotes with porphobilinogen deaminase and uroporphyrinogen decarboxylase deficiencies [22].

Anatomical context of UROD

• We may, therefore, conclude that the porphyrogenic effect of C in monolayers of chick embryo liver cells is the result of its inhibitory effect on the activity of UROD [23].
• Measurements of pulse labeled URO-D in Epstein-Barr virus transformed lymphocytes indicated that the mutant protein has a half-life in vivo of less than four hours [24].
• In vitro measurements utilizing labeled URO-Ds generated in a reticulocyte lysate system revealed a 12-hour half-life for the mutant protein compared with a 102-hour half-life for normal URO-D [24].
• We have also demonstrated that the level of uroporphyrinogen decarboxylase mRNA is markedly increased in tissues or cell lines of erythroid origin and that this is due to a tissue-specific transcriptional activation of the uroporphyrinogen decarboxylase gene [25].
• In agreement with previous studies, we have found that the locus for URO-D is located on chromosome 1 in hybrid cell mapping panels [26].

Associations of UROD with chemical compounds

• The lysine to glutamine at amino acid position 253 was found in conjunction with a single C nucleotide deletion in exon 8 on the same allele of the UROD gene in the same family [1].
• UROD (0.03 nM) also enhanced the guanylin-induced natriuresis (to %ENa(+)=31.0+/-1.93, P<0.05, 120 min) and kaliuresis (to %EK(+)=54.2+/-3.61, P<0.05, 120 min), and inhibited the %ENa(+) of uroguanylin (0.31 muM) to 17.9+/-1.67 as well as its %EK(+) to 24.3+/-3.13 (both at 120 min, P<0.05) [27].
• Atrial natriuretic peptide (ANP) and its renal form (urodilatin, UROD) elicit natriuretic effects by activation of a different membrane guanylate cyclase, GC-A [27].
• Neither ethanol nor estrogen has been shown to cause UROD-deficiency in animals [28].
• No invariant cysteine residues were found, despite the fact that UROD isolated from different sources has been shown to be inhibited by sulfhydryl reagents [29].

Other interactions of UROD

• A coexistent dual enzyme deficiency of PBG-D and URO-D could be confirmed by repeated studies over 10 years [22].
• However, there was no clear correlation between f-PCT disease severity and the URO-D and/or hemochromatosis genotypes [30].
• All but one mutation altered a restriction site in the URO-D gene, permitting identification of affected relatives using a combination of polymerase chain reaction and restriction enzyme digestion [31].
• In contrast to the effects on ALAD, DMSO decreases the activities of porphobilinogen deaminase and uroporphyrinogen decarboxylase [32].
• Experiments were done in perfused rat kidneys to search for possible synergistic interactions between ANP, UROD, guanylin and uroguanylin on renal function [27].

Analytical, diagnostic and therapeutic context of UROD

• To elucidate the UROD defect, we cloned UROD cDNAs from EBV-transformed lymphoblastoid cells of the proband using reverse transcriptase-polymerase chain reaction [2].
• The 3.6-kb URO-D gene was completely sequenced, and a long-range PCR method was developed to amplify the entire gene for mutation analysis [30].
• Molecular cloning and nucleotide sequence of a complete human uroporphyrinogen decarboxylase cDNA [25].
• The use of in situ hybridization allowed us to map the URO-D locus to band 1p34 [26].
• We conclude that reduced red-cell uroporphyrinogen decarboxylase activity is a specific and intrinsic defect in porphyria cutanea tarda; measurement of this enzyme is a reliable diagnostic test for this disease [33].

References