HEREDITARY COPROPORPHYRIA - EXON SCREENING BY HETERODUPLEX ANALYSIS DETECT 3 NOVEL MUTATIONS IN THE COPROPORPHYRINOGEN OXIDASE GENE

Hereditary coproporphyria is a dominantly inherited disorder of porphy rin metabolism caused by a partial deficiency of coproporphyrinogen ox idase, the sixth enzyme in the heme synthetic pathway. We investigated the molecular basis of hereditary coproporphyria in three unrelated p atients, amplifying each exon of the coproporphyrinogen oxidase gene a nd performing heteroduplex analysis to look for mutations. Unique hete roduplex patterns were noted in exons 2, 3, and 6. Sequencing revealed different mutations in each patient: a G-->A point mutation encoding a glutamic acid to lysine substitution at codon 101 (E1O1K), a C-->T p oint mutation encoding a proline to serine substitution at codon 149 ( P149S), and a one base-pair insertion in exon 6 (968insT). No other mu tations were found on se quencing the remaining exons and their intron -exon junctions. The two point mutations affect amino acids that are c onserved in all species studied to date. The one base pair insertion i n exon 6 is the first frameshift mutation to be described in the copro porphyrinogen oxidase gene. This study adds three new mutations to tho se that have been previously reported, and all have been restricted to single families. These results indicate that hereditary coproporphyri a is a genetically heterogeneous disease. (C) 1997 Wiley-Liss, Inc.