In the kindred reported by Nordmann et al. (1983) in which 3 sibs had harderoporphyria (see 121300), Lamoril et al. (1995) found by sequencing cDNA and genomic DNA that the patients carried a point mutation resulting in a LYS304GLU substitution (now known as lys404-to-glu) in exon 6 and the absence of the normal allele, suggesting a homozygous state for the mutation. Enzymatic activity studies of protein expressed from normal and mutated CPO cDNA in E. coli demonstrated that the K404E amino acid substitution was responsible for both the decrease in the enzyme activity and the accumulation of harderoporphyrin. The Michaelis constant of the mutated enzyme was 10-fold higher than normal, suggesting that the lysine at position 304 is important for binding the substrate. A slightly increased sensitivity to thermal denaturation was also observed.
Lamoril et al. (1995) numbered this mutation on the basis of the sequence described by Taketani et al. (1994). Subsequently the mutation was referred to as K404E (Lamoril et al., 1998) based on the initiation codon described by Delfau-Larue et al. (1994).
