Molecular Genetics of Congenital Erythropoietic Porphyria

Abstract

Congenital erythropoietic porphyria (CEP), an autosomal recessive inborn error of heme biosynthesis, results from the markedly deficient activity of the cytosolic enzyme, uroporphyrinogen III synthase (URO-synthase). The accumulation of the nonphysiological and pathogenic porphyrin isomers, uroporphyrin I and coproporphyrin I, leads to the clinical manifestations of CEP. Disease severity in unrelated patients is markedly heterogeneous, ranging from fetal demise or severe transfusion dependency throughout life to milder adult cases with only cutaneous photosensitivity. To date, 18 mutations causing CEP have been described in the URO-synthase gene, including single base substitutions, insertions and deletions, and splicing defects. Most mutations have been identified in one or a few unrelated families with the exception of C73R, L4F, and T228M which occurred in about 33%, 8%, and 7% of the mutant alleles studied, respectively. Prokaryotic expression of the mutant URO-synthase alleles identified those with significant residual activity, thereby permitting genotype/phenotype predictions for severe to milder phenotypes of this clinically heterogeneous disease. As successful bone marrow transplantation in severely affected patients has proven curative, current efforts are underway to develop hematopoietic stem cell gene therapy for CEP.

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

“…In humans defective heme synthesis has been implicated in diseases including anemia and porphyrias [1,4,[92][93][94][95][96][97][98][99][100]. Partially defective ALAS results in sideroblastic anemia, while defects in any of the other enzymes involved in heme biosynthesis results in porphyria [1,[92][93][94][95][96][97][98][99][100]. Porphyrias may be inherited or caused by the intake of chemicals that inhibit the enzymes involved in heme synthesis [92][93][94][95].…”

“…The effect of lead on heme synthesis may be related to the encephalopathy caused by lead poisoning [101]. Porphyrias are associated with skin lesions, neuropathy and hepatic dysfunction [1,[92][93][94][95][96][97][98][99][100]. Neurological manifestations of porphyrias include those associated with disturbances of the CNS, such as anxiety, confusion and depression, and of the autonomic nervous system, such as abdominal pain, vomiting, hypertension and tachycardia [1,[92][93][94][95][96][97][98][99][100].…”

Congenital erythropoietic porphyria: a novel uroporphyrinogen III synthase branchpoint mutation reveals underlying wild-type alternatively spliced transcripts

“…Light activates the photocatalytic URO I and COPRO I isomers, resulting in tissue damage and the formation of bullous cutaneous lesions that rupture, often becoming infected, and lead to bone resorption and cutaneous deformity. 4 The clinical manifestations of CEP are markedly heterogeneous, dependent primarily on the amount of residual UROsynthase activity, and range from nonimmune hydrops fetalis to milder, later-onset forms. 1,4 Severely affected patients are transfusion-dependent throughout life and have splenomegaly and marked cutaneous involvement leading to severe scarring and/or deformities.…”

“…4 The clinical manifestations of CEP are markedly heterogeneous, dependent primarily on the amount of residual UROsynthase activity, and range from nonimmune hydrops fetalis to milder, later-onset forms. 1,4 Severely affected patients are transfusion-dependent throughout life and have splenomegaly and marked cutaneous involvement leading to severe scarring and/or deformities. Additional manifestations may include hypertrichosis, alopecia, and erythrodontia.…”

“…Only the C73R missense mutation is common, occurring in approximately one-third of the CEP alleles studied, whereas the other mutations have been detected in only 1 to 3 presumably unrelated families. 4,6 Most of the missense mutations expressed in Escherichia coli had low activity (Ͻ 2% of wild-type), but several were found to have significant residual activity, which appeared to correlate with the milder, later-onset phenotypes. 4 Disease-causing point mutations in the branchpoint consensus sequence (BPS) are rare.…”