Propionic acidemia (PA, MIM 232000 and 232050) is caused by a deficiency of 
mitochondrial biotin-dependent propionyl-CoA carboxylase (PCC, EC 6.4.1.3), a 
heteropolymeric enzyme composed of alpha and beta subunits, which are encoded by 
the PCCA and PCCB genes, respectively. The PCCA protein (alpha subunit) is 
responsible for the formation of carboxybiotin upon hydrolysis of ATP and 
contains a C-terminal biotin-binding domain and a biotin carboxylase domain, 
defined by homology with other biotin-dependent carboxylases, some of them 
characterized structurally. More than 24 mutations have been found in the PCCA 
gene in patients with PA, among them 14 missense mutations and one in-frame 
deletion, for which the precise molecular effect is unknown. In this study, we 
have established the pathogenicity of 11 PCCA mutations (10 missense and an 
in-frame deletion) by expression studies in deficient fibroblasts and in a 
cell-free in vitro system, and analyzed the effect of each mutation on PCC 
activity, protein stability and domain structure. The results show that most 
mutant proteins show an increased turnover and are functionally deficient, 
suggesting that the structural alterations they cause are incompatible with 
normal assembly to produce a stable, functional PCC oligomer. These results are 
discussed in the context of the genotype-phenotype correlations in 
PCCA-deficient PA patients.