Mutations in the
PCCA or PCCB genes, encoding both subunits of
propionyl-CoA carboxylase, result in
propionic acidemia, a life-threatening inborn error of metabolism with autosomal recessive inheritance. To date, 41 mutations in the
PCCA gene and 54 in the PCCB gene have been reported, most of them single base substitutions causing
amino acid replacements, and a variety of small insertions and deletions and splicing defects. A greater heterogeneity is observed in the
PCCA gene, specially in Caucasians, with no prevalent mutations, while in the Japanese population three mutations account for more than half of the alleles studied. For the PCCB gene a limited number of mutations is responsible for the majority of the alleles characterized in both Caucasian and Oriental populations. These two populations show a different mutational spectrum, only sharing some involving CpG dinucleotides probably as recurrent mutational events. Functional characterization of the mutant missense alleles has been accomplished using different prokaryotic and eukaryotic systems, and the structural consequences have been analyzed in the available crystal models. For the
PCCA gene, the main molecular effect of the expressed mutations is related to
protein instability, except two mutations in the active site predictably affecting
ATP binding. In the PCCB gene the majority of the analyzed mutations are predicted to alter the active site conformation resulting in diminished activity. A few carboxy-terminal PCCB mutations affect the interaction between subunits and the assembly with
PCCA to form a functional PCC oligomer. The amount of normal transcripts resulting from some
PCCA and PCCB splicing mutations has also been analyzed. Overall, the data generated from the expression analysis reveal potential genotype-phenotype correlations for this clinically heterogeneous disorder.