title: High frequency of large genomic deletions in the PCCA gene causing propionic acidemia.
abstract: Mutations in either the PCCA or PCCB genes are responsible for propionic acidemia (PA), one of the most frequent organic acidemias inherited in autosomal recessive fashion. Most of the mutations detected to date in both genes are missense. In the case of PCCA deficient patients, a high number of alleles remain uncharacterized, some of them suspected to carry an exonic deletion. We have now employed multiplex ligation probe amplification (MLPA) and long-PCR in some cases to screen for genomic rearrangements in the PCCA gene in 20 patients in whom standard mutation detection techniques had failed to complete genotype analysis. Eight different deletions were found, corresponding to a frequency of 21.3% of the total PCCA alleles genotyped at our center. Two of the exonic deletions were frequent, one involving exons 3-4 and another exon 23 although in the first case two different chromosomal breakpoints were identified. Absence of exons 3 and 4 which is also the consequence of the novel splicing mutation c.231+1g>c present in two patients, presumably results in an in-frame deletion covering 39 aminoacids, which was expressed in a eukaryotic system confirming its pathogenicity. This work describes for the first time the high frequency of large genomic deletions in the PCCA gene, which could be due to the characteristics of the PCCA gene structure and its abundance in intronic repetitive elements. Our data underscore the need of using gene dosage analysis to complement routine genetic analysis in PCCA patients.
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, UAM-CSIC, Departamento de Biología Molecular, Universidad Autónoma de Madrid, ISCIII, Madrid, Spain. lruiz@cbm.uam.es
authors.forename: Lourdes R
authors.initials: LR
authors.lastname: Desviat
authors.forename: Rocío
authors.initials: R
authors.lastname: Sanchez-Alcudia
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.forename: Celia
authors.initials: C
authors.lastname: Pérez-Cerdá
authors.forename: Rosa
authors.initials: R
authors.lastname: Navarrete
authors.forename: Raymon
authors.initials: R
authors.lastname: Vijzelaar
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D001483:Base Sequence; D019457:Chromosome Breakage; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology; D015894:Genome, Human / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D043586:Methylmalonyl-CoA Decarboxylase / Q000235:genetics*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011422:Propionates / Q000097:blood*; D017384:Sequence Deletion / Q000235:genetics*; D014162:Transfection
chemical_list: D050505:Mutant Proteins; D011422:Propionates; D043586:Methylmalonyl-CoA Decarboxylase