Propionic acidemia is an inborn error of metabolism caused by a deficiency
of propionyl-CoA carboxylase, a heteropolymeric mitochondrial enzyme involv
ed in the catabolism of branched chain amino acids, odd-numbered chain leng
th fatty acids, cholesterol, and other metabolites, The enzyme is composed
of alpha and beta subunits which are encoded by the PCCA and PCCB genes, re
spectively. Mutations in both genes can cause propionic acidemia. The ident
ification of the responsible gene, previous to mutation analysis, can be pe
rformed by complementation assay or, in some instances, can be deduced from
peculiarities relevant to either gene, including obtaining normal enzyme a
ctivity in the parents of many patients with PCCB mutations, observing comb
ined absence of alpha and beta subunits by Western blot of many PCCA patien
ts, as well as conventional mRNA minus result of Northern blots for either
gene or beta subunit deficiency in PCCB patients. Mutations in both the PCC
A and PCCB genes have been identified by sequencing either RT-PCR products
or amplified exonic fragments, the latter specifically for the PCCB gene fo
r which the genomic structure is available. To date, 24 mutations in the PC
CA gene and 29 in the PCCB gene have been reported, most of them single bas
e substitutions causing amino acid replacements and a variety of splicing d
efects, A greater heterogeneity is observed in the PCCA gene-no mutation is
predominant in the populations studied-while for the PCCB gene, a limited
number of mutations is responsible for the majority of the alleles characte
rized in both Caucasian and Oriental populations. These two populations sho
w a different spectrum of mutations, only sharing some involving CpG dinucl
eotides, probably as recurrent mutational events. Future analysis of the mu
tations identified, of their functional effect and their clinical relevance
, will reveal potential genotype-phenotype correlations for this clinically
heterogeneous disorder. Hum Mutat 14:275-282, 1999, (C) 1999 Wiley-Liss, I
nc.