HOMOZYGOUS HEREDITARY COPROPORPHYRIA CAUSED BY AN ARGININE TO TRYPTOPHANE SUBSTITUTION IN COPROPORPHYRINOGEN OXIDASE AND COMMON INTRAGENIC POLYMORPHISMS

Coproporphyrinogen oxidase is a mitochondrial heme-biosynthetic enzyme that converts coproporphyrinogen to protoporphyrinogen. Inherited def iciency of this enzyme causes the human genetic disease hereditary cop roporphyria. Recently, we isolated, sequenced and expressed the cDNA e ncoding human coproporphyrinogen oxidase. This allowed us to investiga te the nature of the defect leading to a profound deficiency of coprop orphyrinogen oxidase in a patient with homozygous hereditary coproporp hyria. Using reverse-transcription, amplification of the cDNA and dire ct sequencing of the amplified products, we found a point mutation res ulted in an arginine to tryptophane substitution (R231W). Expression s tudies of normal and mutated cDNAs in a bacterial system demonstrated that this substitution resulted in the synthesis of an unstable protei n with a residual catalytic activity. This is the first mutation to be found at the coproporphyrinogen oxidase locus. Furthermore, three com mon polymorphisms within the coproporphyrinogen oxidase gene were dete cted. Two DNA polymorphisms resulted in amino acids changes (H172N and V194I) and the third one was silent (E230E).