The inherited metabolic disease propionic acidemia (PA) can result from 
mutations in either of the genes PCCA or PCCB, which encode the alpha and beta 
subunits, respectively, of the mitochondrial enzyme propionyl CoA-carboxylase. 
In this work we have analyzed the molecular basis of PCCA gene defects, studying 
mRNA levels and identifying putative disease causing mutations. A total of 10 
different mutations, none predominant, are present in a sample of 24 mutant 
alleles studied. Five novel mutations are reported here for the first time. A 
neutral polymorphism and a variant allele present in the general population were 
also detected. To examine the effect of a point mutation (M348K) involving a 
highly conserved residue, we have carried out in vitro expression of normal and 
mutant PCCA cDNA and analyzed the mitochondrial import and stability of the 
resulting proteins. Both wild-type and mutant proteins were imported into 
mitochondria and processed into the mature form with similar efficiency, but the 
mature mutant M348K protein decayed more rapidly than did the wild-type, 
indicating a reduced stability, which is probably the disease-causing mechanism.