Three independent mutations in the same exon of thePCCB gene: Differences between Caucasian and Japanese propionic acidaemia

Summary

Propionic acidaemia is an inborn error of organic acid metabolism caused by deficiency of propionyl-CoA carboxylase (PCC). Enzyme deficiency can result from mutations in either of the non-identical α- and β-subunits. We have screened genomic DNA from patients with defects in the β-subunit from two ethnic groups (Caucasians and Japanese) and detected three types of mutations in the same exon of the coding sequence of the β-subunit: an insertion/deletion that replaces 14 nucleotides with 12 nucleotides of unrelated sequence and eliminates anMsp I site; a 3-bp deletion of a single isoleucine codon immediately proximal to thatMsp I site; and a C → T transition in the sameMsp I site. The insertion/deletion was detected only in Caucasian patients in 11 of 34 mutant alleles; the C → T transition was found only in Japanese patients in 4 of 12 mutant alleles. Following digestion of genomic DNA byMsp I, both of these mutations were detected on Southern blots by the presence of a 2.7-kbp band; they can be distinguished from one another by allele-specific oligonucleotide hybridization following PCR amplification. These results underscore the independent origin of the mutations in the two populations and suggest a key role of this exon in the β-subunit of PCC.