title: Mutations in the translation initiation codon of the protoporphyrinogen oxidase gene underlie variegate porphyria.
abstract: Variegate porphyria (VP), one of the acute hepatic porphyrias, is characterized by a reduced catalytic activity of protoporphyrinogen oxidase (PPO), the penultimate enzyme in the porphyrin-haem biosynthetic pathway. VP has been linked to the PPO gene on chromosome 1q22-23, and several mutations underlying this disorder have been described recently. In this study, we identified two different missense mutations in the translation initiation codon of the PPO gene in two unrelated patients with VP. Mutation analysis was carried out using PCR, heteroduplex analysis, automated sequencing, and restriction enzyme digestion. In the first patient, the results revealed an A-to-T transversion (ATG --> TTG), resulting in the substitution of methionine by leucine (M1L). The mutation detected in the second patient was a T-to-C transition (ATG --> ACG), leading to the conversion of methionine to threonine (M1T). These mutations abolish the initiation of translation at the normal site, and consequently, translation of an abnormal messenger RNA (mRNA) would result in the synthesis of a truncated PPO protein lacking the amino terminus.
authors.affiliation: Department of Dermatology, Columbia University, New York, New York 10032, USA.
authors.forename: J
authors.initials: J
authors.lastname: Frank
authors.forename: J A
authors.initials: JA
authors.lastname: McGrath
authors.forename: M B
authors.initials: MB
authors.lastname: Poh-Fitzpatrick
authors.forename: J L
authors.initials: JL
authors.lastname: Hawk
authors.forename: A M
authors.initials: AM
authors.lastname: Christiano
mesh_terms: D000241:Adenosine / Q000235:genetics; D000328:Adult; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D018387:Codon, Initiator / Q000235:genetics*; D003596:Cytosine; D005260:Female; D005420:Flavoproteins; D006801:Humans; D007930:Leucine / Q000235:genetics; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D024101:Mitochondrial Proteins; D020125:Mutation, Missense / Q000235:genetics*; D009692:Nucleic Acid Heteroduplexes / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D017354:Point Mutation / Q000235:genetics; D017094:Porphyrias, Hepatic / Q000201:enzymology* / Q000235:genetics; D011166:Porphyrins / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D050768:Protoporphyrinogen Oxidase; D012333:RNA, Messenger / Q000235:genetics; D013912:Threonine / Q000235:genetics; D013941:Thymine
chemical_list: D018387:Codon, Initiator; D005420:Flavoproteins; D024101:Mitochondrial Proteins; D009692:Nucleic Acid Heteroduplexes; D011166:Porphyrins; D012333:RNA, Messenger; D013912:Threonine; D003596:Cytosine; D008715:Methionine; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C493978:PPOX protein, human; D050768:Protoporphyrinogen Oxidase; D007930:Leucine; D000241:Adenosine; D013941:Thymine