AN UNUSUAL INSERTION DELETION IN THE GENE ENCODING THE BETA-SUBUNIT OF PROPIONYL-COA CARBOXYLASE IS A FREQUENT MUTATION IN CAUCASIAN PROPIONIC ACIDEMIA

Propionic acidemia is an inherited disorder of organic acid metabolism that is caused by deficiency of propionyl-CoA carboxylase (PCC; EC 6.4.1.3). Affected patients fall into two complementation groups, pccA and pccBC (subgroups B, C, and BC), resulting from deficiency of the nonidentical α and β subunits of PCC, respectively. We have detected an unusual insertion/deletion in the DNA of patients from the pccBC and pccC subtroups that replaces 14 nucleotides in the coding sequence of the β subunit with 12 nucleotides unrelated to this region of the gene. This results in elimination of an Msp I restriction site, a 2-base-pair (bp) deletion, a frameshift, and a stop codon in the new frame ~ 100 amino acid residues proximal to the normal carboxyl terminus. Among 14 unrelated Caucasian patients in the pccBC complementation group, this unique mutation was found in 8 of 28 mutant alleles examined. Mutant allele-specific oligonucleotide hybridization to amplified genomic DNAs revealed that the inserted 12 nucleotides do not originate in an ~ 1000-bp region around the mutation. In the course of our investigation, we identified another mutation in the same exon: a 3-bp in-frame deletion that eliminates one of two isoleucine codons immediately preceding the Msp I site. Two unrelated patients were compound heterozygotes for this single-codon deletion and for the insertion/deletion described above. We conclude that either there is a propensity for the PCC β-subunit gene to undergo mutations of this sort at this position or, more likely, the mutations in all of the involved Caucasian patients have a common origin in preceding generations.