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Winning Abstracts from the 2007 Medical Student Abstract Competition: Porphyria Cutanea Tarda (Pct): Mutations and Sequence Variants in the Uroporphyrinogen Decarboxylase (Uro-D) Gene in Sporadic Patients.


Eric Gehrie, Mount Sinai School of Medicine

Porphyria cutanea tarda (PCT), the most common disorder of heme biosynthesis, typically presents with characteristic light-induced blistering skin lesions. Familial PCT (F-PCT) is an autosomal dominant disorder and patients have germline uroporphyrinogen decarboxylase (URO-D) mutations, half-normal erythrocyte and decreased hepatic URO-D activities. In contrast, sporadic PCT (S-PCT) patients have normal UROD genes and erythrocyte URO-D activities, but have decreased hepatic URO-D activity presumably due to the specific inhibition of the hepatic enzyme. Both familial and sporadic forms are precipitated by environmental factors including alcohol, iron overload, and viral infections (e.g., HCV). S-PCT and F-PCT can be diagnosed biochemically by markedly elevated urinary heptacarboxylate porphyrin levels.

To determine if URO-D single nucleotide polymorphisms (SNPs) or rare sequence variants predispose to S-PCT, the entire ~3.5 kb URO-D gene and 1000 bases upstream and downstream were sequenced in 24 sporadic patients who had no affected relatives, and 25 unrelated normal individuals.

Surprisingly, two previously identified URO-D coding mutations, R142X and a complex mutation (g645del1053ins10), were identified in 2 (8.3%) unrelated S-PCT patients, indicating that they actually had F-PCT. At-risk relatives have been counseled and offered testing. In addition, studies of a known F-PCT family revealed a novel URO-D mutation (H331R). Among the 22 S-PCT patients, 8 SNPs were identified at gDNA -293 (4 patients), -263 (9), -175 (1),496 (9), 1562 (2), 1772 (2), 1835 (9), and 2892 (9). The three F-PCT patients had 5 SNPs at gDNA -263 (2), 496 (10), 1835 (2), 2892 (2), and 3236 (1). In the 25 control patients, 7 SNPs were identified at gDNA -293 (6), -263 (10), 496 (10), 1562 (2), 1772 (2), 1835 (10), and 2892 (10).

This is the first report of germline mutations in presumed S-PCT patients, indicating that these manifesting patients either had de novo mutations or F-PCT that masqueraded as S-PCT due to the low penetrance of the germline mutations. Therefore, biochemically confirmed S-PCT patients should be screened by mutation analysis. In addition, no sequence variants or SNPs were identified in the URO-D gene that predisposed patients to S-PCT.

Back to October 2007 Issue of IMpact

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