title: Overview of mutations in the PCCA and PCCB genes causing propionic acidemia.
abstract: Propionic acidemia is an inborn error of metabolism caused by a deficiency of propionyl-CoA carboxylase, a heteropolymeric mitochondrial enzyme involved in the catabolism of branched chain amino acids, odd-numbered chain length fatty acids, cholesterol, and other metabolites. The enzyme is composed of alpha and beta subunits which are encoded by the PCCA and PCCB genes, respectively. Mutations in both genes can cause propionic acidemia. The identification of the responsible gene, previous to mutation analysis, can be performed by complementation assay or, in some instances, can be deduced from peculiarities relevant to either gene, including obtaining normal enzyme activity in the parents of many patients with PCCB mutations, observing combined absence of alpha and beta subunits by Western blot of many PCCA patients, as well as conventional mRNA-minus result of Northern blots for either gene or beta subunit deficiency in PCCB patients. Mutations in both the PCCA and PCCB genes have been identified by sequencing either RT-PCR products or amplified exonic fragments, the latter specifically for the PCCB gene for which the genomic structure is available. To date, 24 mutations in the PCCA gene and 29 in the PCCB gene have been reported, most of them single base substitutions causing amino acid replacements and a variety of splicing defects. 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 characterized in both Caucasian and Oriental populations. These two populations show a different spectrum of mutations, only sharing some involving CpG dinucleotides, probably as recurrent mutational events. Future analysis of the mutations identified, of their functional effect and their clinical relevance, will reveal potential genotype-phenotype correlations for this clinically heterogeneous disorder.
authors.affiliation: Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Madrid, Spain. mugarte@cbm.uam.es
authors.forename: M
authors.initials: M
authors.lastname: Ugarte
authors.forename: C
authors.initials: C
authors.lastname: Pérez-Cerdá
authors.forename: P
authors.initials: P
authors.lastname: Rodríguez-Pombo
authors.forename: L R
authors.initials: LR
authors.lastname: Desviat
authors.forename: B
authors.initials: B
authors.lastname: Pérez
authors.forename: E
authors.initials: E
authors.lastname: Richard
authors.forename: S
authors.initials: S
authors.lastname: Muro
authors.forename: E
authors.initials: E
authors.lastname: Campeau
authors.forename: T
authors.initials: T
authors.lastname: Ohura
authors.forename: R A
authors.initials: RA
authors.lastname: Gravel
mesh_terms: D017398:Alternative Splicing; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D002262:Carboxy-Lyases / Q000235:genetics*; D016368:Frameshift Mutation; D006801:Humans; D046911:Macromolecular Substances; D043586:Methylmalonyl-CoA Decarboxylase; D009154:Mutation; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D011422:Propionates / Q000097:blood*; D017384:Sequence Deletion
chemical_list: D046911:Macromolecular Substances; D011422:Propionates; D002262:Carboxy-Lyases; D043586:Methylmalonyl-CoA Decarboxylase