Uroporphyrinogen Decarboxylase Structural Mutant (Gly281→Glu) in a Case of Porphyria

Abstract

Uroporphyrinogen decarboxylase deficiency in man is responsible for familial porphyria cutanea tarda and hepatoerythropoietic porphyria. A recent study of a family with hepatoerythropoietic porphyria showed that the enzyme defect resulted from rapid degradation of the protein in vivo. Cloning and sequencing of a complementary DNA for the mutated gene revealed that the mutation was due to the replacement of a glycine residue by a glutamic acid residue at position 281. This base change leads to a protein that is very rapidly degraded in the presence of cell lysate. Characterization of the mutation will allow comparison of this defect in a homozygous patient with defects in other patients with familial porphyria cutanea tarda.

Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase

“…[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.…”

“…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).…”

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

“…Mutations in the uroporphyrinogen decarboxylase gene (UROD; MIM# 176100) are associated with familial porphyria cutanea tarda (fPCT) (Garey et al 1989, Garey et al 1990, Roberts et al 1995, Moran-Jimenez et al 1996, McManus et al 1996 and hepatoerythropoietic porphyria (HEP) (de Verneuil et al 1986, Romana et al1991, de Verneuil et al 1992, Meguro et al 1994, Moran-Jimenez et al 1996, McManus et al 1996. These include missense, nonsense and splice junction mutations as well as deletions and it would seem that the genetic causes of fPCT and HEP are heterogeneous.…”

A mouse model of familial porphyria cutanea tarda

“…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).…”