ERYTHROPOIETIC PROTOPORPHYRIA--MECHANISMS OF DISEASE

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DESCRIPTION (Adapted from the applicant's abstract): Human protoporphyria is a genetically determined metabolic defect in heme biosynthesis. Partial deficiency in the activity of the enzyme ferrochelatase (FC) in bone marrow erythroid cells results in accumulation of protoporphyrin (PP) in rbc, plasma, liver, and feces. PP causes painful cutaneous photosensitivity and may lead to fatal hepatotoxicity in affected children and adults. Much remains unknown about the natural course of human protoporphyria and about its disease mechanisms in skin, bone marrow, and liver. Continuation of ongoing longitudinal investigations of an established protoporphyria study population with a standardized protocol that has already built a data base for 8 years or longer in the majority of 24 currently participating patients, will further advance current understanding of how this disease evolves in a large number of carefully studied individual patients over many years of time. Individual patients may benefit from early detection of adverse changes in hepatic function. Factors leading to development of fatal hepatotoxicity may be learned from retrospective analysis of the accumulated data base for patients who develop liver dysfunction when compared with the data of the population as a whole. Elucidation of the structure and function of human FC will be advanced by biochemical and immunological methods. Purified FC protein produced by novel chromatographic methods that the investigators have already developed will be used to produce polyclonal and monoclonal antibodies useful for characterization studies of mutant versus normal human FCs proposed herein. Development of such immunological reagents and of oligonucleotide probes constructed according to amino acid sequence information derived from peptides cleaved from purified human FC will enable them, in future years, to propose to clone and express the gene for human FC, to initiate a search for its chromosomal assignment, and to determine the precise nature of the FC mutation responsible for human protoporphyria. In vivo stability of FC in bone marrow will be evaluated first in drug-induced rat erythropoiesis and myelopoiesis models, then in human protoporphyric bone marrow. Clinical and laboratory evaluations of unusual cases of several related forms of porphyria that have already provided new information regarding this group of diseases will be continued. In particular, immunomapping of the microanatomical level of the epidermal-dermal separation in porphyria cutanea tarda will be carried out to target appropriate biomolecular components of the basement membrane zone for further study.