Thesis or Dissertation Basic and clinical investigations on patients with porphyrias: Congenital Erythropoietic Porphyria, Hereditary Coproporphyria and Harderoporphyria


Of eight inherited porphyria diseases in the heme-biosynthetic pathway, my study provides an understanding of a very rare disease which is the first description of a mutation in the UROS gene in a Southeast Asian patient and a molecular diagnosis for the identification of clinically asymptomatic heterozygous mutation carriers and families with CEP. A missense mutation in the UROS gene was identified as a transversion of G to T at nucleotide 11,776, resulting in a substitution of valine by phenylalanine at codon 3 of exon 2. The patient showed a homozygous mutant profile, and the heterozygous state was observed in the parents. The activity of mutated UROS expressed in E. coli was less than 16.1% that of the control, indicating that the markedly reduced activity of UROS is responsible for CEP. Second, I clarified responsibility of different phenotypes between HCP and harderoporphyria, both of which are the mutations of the same enzyme, CPOX. The monomer form of mutated CPOX did not show any activity and homodimeric enzymes derived from HCP mutant showed low activity (<20% of the control). Some mutations of amino acids 401-404 were associated with marked accumulation of harderoporphyrinogen, with decrease in the production of protoporphyrinogen, whereas K404E derived from patients with harderoporphyria produced less harderoporphyrinogen. The heterodimers with wt and mutated subunits from HCP patients showed low protoporphyrinogen producing activity. My results show that the substitution of amino acids from R401 to K404 results in extremely low enzyme activity with either mutant homodimer or heterodimers containing normal and mutated subunits and can be linked to HCP disease. Furthermore, the types and positions of mutationts in the human CPOX gene may predict the clinical outcome of the disesease with manifestations of HCP or harderoporphyrinnogen. Herein, I provided evidence that the mutant homodimer results in harderoporphyria and heterodimer leads to HCP

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