Molecular genetics of congenital erythropoietic porphyria

Congenital erythropoietic porphyria (CEP), an autosomal recessive inborn er ror of heme biosynthesis, results from the markedly, deficient activity of the cytosolic enzyme, uroporphyrinogen III synthase (URO-synthase). The acc umulation of the nonphysiological and pathogenic porphyrin isomers, uroporp hyrin I and coproporphyrin I. leads to the clinical manifestations of CEP. Disease severity in unrelated patients is markedly heterogeneous, ranging f rom fetal demise or severe transfusion dependency throughout life to milder adult cases with only cutaneous photosensitivity. To dare, 18 mutations ca using CEP have been described in the URO-synthase gene, including single ba se substitutions, insertions and deletions, and splicing defects. Most muta tions have been identified in one or a few unrelated families with the exce ption of C73R, L4F, and T228M which occurred in about 33%, 8%, and 7% of th e mutant alleles studied, respectively. Prokaryotic expression of the mutan t URO-synthase alleles identified those with significant residual activity, thereby permitting genotype/phenotype predictions for severe to milder phe notypes of this this clinically heterogeneous disease. As successful bone m arrow transplantation in severely affected patients has proven curative, cu rrent efforts are underway to develop hematopoietic stein cell gene therapy for CEP.