Three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda

McManus, J. F.; Begley, C. Glenn; Sassa, Shigeru; Ratnaike, Sujiva

doi:10.1002/(sici)1098-1004(1999)13:5<412::aid-humu11>3.0.co;2-t

Cited by 16 publications

(20 citation statements)

References 19 publications

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“…The Ala80Ser mutation was previously detected by Brady et al, 12 but properties of the mutant enzyme were not determined. A second mutation at the same residue, Ala80Gly, has been described by McManus et al, 9 who reported the catalytic activity of recombinant Ala80Gly URO-D to range from 19% to 39% of normal, values similar to the 33% activity we found for recombinant Ala80Ser URO-D. Ala80 is located at the N-terminal end of the S2 ␤-strand buried with other hydrophobic side chains below the active site. The predicted effect of the Ala80Ser mutation would be disruption of the hydrophobic core, causing conformational changes that could propagate to alter the structure at the base of the active site.…”

Section: Mutations In Human Uro-d 3183supporting

confidence: 85%

“…[3][4][5][6][7][8][9][10][11][12][13][14] Ten of these mutant alleles are predicted to generate shorter proteins as a result of a premature stop codon or a variation in a splice site. [3][4][5][6][7][8][9][10][11][12][13] The remaining 20 previously reported mutations are missense mutations listed in Table 4 and mapped onto the URO-D monomer in Figure 3C. The structural location of these mutations and the predicted structural effects are described in Table 4.…”

Section: Other Uro-d Mutationsmentioning

confidence: 99%

“…More than 30 different URO-D mutations have been identified in unrelated patients. [3][4][5][6][7][8][9][10][11][12][13][14] Most carriers of mutant URO-D alleles do not express clinical phenotypes unless additional factors are present that further reduce the activity of URO-D in the liver. 15,16 Factors shown to be important include alcohol abuse, exposure to the hepatitis C virus, use of medicinal estrogens, and development of hepatic siderosis (often caused by mutation of the hemochromatosis gene).…”

Section: Introductionmentioning

confidence: 99%

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Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase

Phillips

Parker

Schubert

et al. 2001

Blood

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Functional consequences of 12 mutations-10 missense, 1 splicing defect, and 1 frameshift mutation-were characterized in the uroporphyrinogen decarboxylase (URO-D) gene found in Utah pedigrees with familial porphyria cutanea tarda (F-PCT). 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. In a bacterial expression system, 3 of the missense mutants were found in inclusion bodies, but 7 were expressed as soluble proteins. Enzymatic activity of soluble, recombinant mutant URO-D genes ranged from 29% to 94% of normal. URO-D mRNA levels in Epstein-Barrvirus transformed cells derived from patients were normal (with the exception of the frameshift mutation) even though protein levels were lower than normal, suggesting that missense mutations generally cause unstable URO-Ds in vivo. The crystal structures of 3 mutant URO-Ds were solved, and the structural consequences of the mutations were defined. All missense mutations reported here and by others were mapped to the crystal structure of URO-D, and structural effects were predicted. These studies define structural and functional consequences of URO-D mutations occurring in patients with F-PCT. (Blood. 2001;98:3179-3185)

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Section: Mutations In Human Uro-d 3183supporting

confidence: 85%

Section: Other Uro-d Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase

Phillips

Parker

Schubert

et al. 2001

Blood

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“…Environmental factors such as alcohol abuse, hepatitis C virus, and estrogen use also play a role in clinical expression (1,5). Numerous mutations of the URO-D gene have been identified in patients with F-PCT (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) but the most common is a splice-site mutation resulting in the deletion of exon 6 (16).…”

mentioning

confidence: 99%

A mouse model of familial porphyria cutanea tarda

Phillips¹

2000

Proceedings of the National Academy of Sciences

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“…About 20% of patients with PCT have the familial or type II form in which halfnormal UROD activity is present in all tissues and inherited in an autosomal dominant pattern. These patients have mutations in the UROD gene, most of which are restricted to one or a few families (4,20). Most of the other 80% of patients with PCT have the sporadic or type I form in which decreased UROD activity is restricted to the liver.…”

Section: Porphyria Cutanea Tarda and Hepatoerythropoietic Porphyriamentioning

confidence: 99%

Update on enzyme and molecular defects in porphyria

Elder

1998

Photoderm Photoimm Photomed

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Each porphyria results from decreased activity of one of the enzymes of haem biosynthesis. The molecular basis of enzyme deficiencies in acute intermittent porphyria (AIP), variegate porphyria (VP) and congenital erythropoietic porphyria (CEP) is outlined. All three conditions show extensive allelic heterogeneity. In the autosomal dominant disorders, AIP and VP, no genotype/phenotype correlations have been demonstrated, and the explanation for their low clinical penetrance remains uncertain. In AIP and VP, mutational analysis is superior to biochemical methods for screening families for latent porphyria. In the autosomal recessive condition, CEP, there is some genotype/phenotype correlation -one common mutation (C73R) being associated with severe disease in homozygotes. Porphyria cutanea tarda (PCT) is not a simple monogenic disorder.

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Three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda

Cited by 16 publications

References 19 publications

Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase

Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase

A mouse model of familial porphyria cutanea tarda

Update on enzyme and molecular defects in porphyria

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