Blood, 1 December 2001, Vol. 98, No. 12, pp. 3177-3177
"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.
Shigeru Sassa
The Rockefeller
University
