“Affenmensch” defect defined

Porphyria cutanea tarda (PCT) is the most common form of the porphyria and occurs both in inherited and acquired forms. Uroporphyrinogen decarboxylase (URO-D) deficiency is responsible for all PCT. Adult patients are often called “Affenmensch,” and younger patients, “monkey children,” because of the immense pigmentation and hypertrichosis due to porphyrin-induced photosensitivity that occur particularly on the face and extremities.

Phillips and colleagues (page 3179) report the first structural analysis of URO-D mutants in the familial form of PCT (fPCT) and define their functional consequences. They have studied 12 URO-D mutants by bacterial expression and have found some as insoluble, while most others as soluble, proteins. Three soluble mutant proteins were then subjected to X-ray crystallographic analysis. There are 3 important points that merit particular mention in their study. First, crystal structures of the 3 URO-D mutants demonstrated a common structural change, the disorder of a surface loop. Second, most of the mutations lie near the URO-D dimer interface, suggesting that disruption of the dimer interface may be critical for enzymatic activity. Third, none of the mutations were lethal; that is, they were “conservative” and had significant residual activity. These findings thus define the structural basis of the functional significance of URO-D mutations in fPCT and also permit prediction why 30 other URO-D mutants reported elsewhere may be associated with low enzyme activity.

fPCT is an intriguing genetic disease in that not only the URO-D defect but also various other factors may play a role in its pathogenesis, for example, alcohol, iron, and estrogen. Recent evidence also suggests that an inhibitor of hepatic URO-D may be generated and involved in clinical expression of PCT. Perhaps some day, structural analysis of the PCT defect might also uncover an influence of these accessory factors on the structure of URO-D.