The molecular defect in propionic acidemia: Exon skipping caused by an 8-bp deletion from an intron in the PCCB allele

Ohura, Toshihiro; Ogasawara, Masahito; Ikeda, Hiroyuki; Narisawa, Kuniaki; Tada, Keiya

doi:10.1007/bf01247343

Cited by 21 publications

(5 citation statements)

References 18 publications

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“…The gene for the α subunit (PCCA) is on chromosome 13q32 and encodes a polypeptide of 703 amino acids, while that for the β subunit (PCCB) is on chromosome 3q13.3-q22 and encodes a polypeptide of 539 amino acids (Lamhonwah 1986;Ohura et al 1993b;Stancovics 1993). A recent review by Ugarte et al (1999) summarized 53 mutations identified in patients with propionic acidemia, 24 in the PCCA gene and 29 in the PCCB gene.…”

Section: Introductionmentioning

confidence: 99%

Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications

et al. 2002

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Propionic acidemia [MIM 606054] is a form of organic acidemia caused by genetic deficiency of propionyl-CoA carboxylase (PCC) and characterized by attacks of severe metabolic acidemia and hyperammonemia beginning in the neonatal period or in early infancy. There are, however, patients who have higher PCC activities and present later with unusual symptoms, such as mild mental retardation or extrapyramidal symptoms, sometimes even without metabolic acidosis. Through the neonatal screening of more than 130,000 Japanese newborns we detected a frequency of patients with propionic acidemia more than ten times higher than previously reported, most of them with milder phenotypes. The mutational spectrum was quite different from that of patients with the severe form and there was a common mutation (Y435C) in the beta subunit of the PCC gene (PCCB). Since patients with the mild form could present with unusual symptoms and therefore could easily remain unrecognized, it is important to identify those patients and clarify their natural history. Molecularly, one of the mutations (A1288C) caused an unusual pattern of multiple exon skipping and another unidentified mutation lead to the absence of mRNA. Taking into consideration previous findings regarding PCCB mutations, it appears that this gene is particularly prone to posttranscriptional modifications such as missense mediated exon skipping, mRNA decay, or rapid product degradation.

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Section: Introductionmentioning

confidence: 99%

Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications

et al. 2002

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“…With identification of the defective gene, cell lines can be analyzed for mutation by conventional techniques. Several mutations have been identified in the PCCB gene (5)(6)(7)(8)(9)(10)(11)(12)(13)(14), while only recently mutations in the PCCA gene have begun to be described (15).…”

Section: Introductionmentioning

confidence: 99%

Detection of a normally rare transcript in propionic acidemia patients with mRNA destabilizing mutations in the PCCA gene

Campeau

Dupuis

Leclerc

et al. 1999

Human Molecular Genetics

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Propionic acidemia is an autosomal recessive disorder caused by a deficiency in the mitochondrial enzyme propionyl-CoA carboxylase (PCC). PCC is composed of two subunits, alpha and beta, encoded by the PCCA and PCCB genes, respectively. We analyzed mutations of the PCCA gene using patients' fibroblasts diagnosed with alpha subunit deficiency. By RT-PCR, four of 12 cell lines examined appeared to have a larger transcript present at a level comparable with that of the expected normal species. Sequencing of the larger transcriptrevealed an 84 bp insertion at nt 1209 of the codingsequence. Its incorporation in the transcript results in translation termination due to the presence of two in-frame stop codons. The 84 bp insertion was found to originate from the intron between nt 1209 and 1210. Consensus splice donor and acceptor sites were found at the 3'- and 5'-ends of the insertion, respectively. The insertion was also found in the remaining eight cell lines as well as in normal cells, but at a muchreduced level compared with the normal lengthsequence. Mutation analysis of the four cell lines showing seemingly elevated levels of the insertion sequence revealed one nonsense mutation (R288X), two frameshift deletions (700del5 and 1115del4) and one splice mutation (1671IVS+5G-->C) as expressed alleles. We conclude that the common characteristic of the four cell lines is that they contain mRNA destabilizing mutations that reduce the mRNA level of the normal length sequence. Consequently, the low levels of cryptic mRNAs become detectable at a level similar to that of the residual level of the normal length mRNA. We suggest that screening for an increased proportion of the 84 bp insertion by RT-PCR can be used as a rapid assay for RNA destabilizing mutations. Our results suggest caution in associating such mutations with aberrant mRNA species, such as cryptic splice products, which may instead be part of the 'background noise' of the splicing machinery.

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“…Enzyme deficiency can result from mutations in either the PCCA or the PCCB genes, defining the two major complementation groups, pccA and pccBC. Full-length cDNAs for the α and β subunits have been cloned and sequenced (Lamhonwah et al 1989(Lamhonwah et al , 1994Ohura et al 1993;Stankovics and Ledley 1993). The PCCA cDNA contains an open reading frame of 2106 nucleotides coding for 702 amino acids and the PCCB cDNA contains an open reading frame of 1617 nucleotides encoding a 539-amino acid polypeptide.…”

Section: Introductionmentioning

confidence: 99%

Three novel splice mutations in the PCCA gene causing identical exon skipping in propionic acidemia patients

et al. 1997

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Propionyl-CoA carboxylase (PCC) is a mitochondrial, biotin-dependent enzyme involved in the catabolism of branched chain amino acids, odd chain fatty acids, and other metabolites. PCC consists of non-identical subunits, alpha and beta, encoded by the PCCA and PCCB genes, respectively. Inherited deficiency of PCC due to mutations in either the PCCA or the PCCB gene results in propionic acidemia (PA), a clinically heterogeneous disorder with a severe, often lethal, neonatal form, and a mild, later onset form. To characterize PCCA gene mutations responsible for PCC deficiency, we analyzed RT-PCR products obtained from cultured fibroblasts from Spanish PCC-alpha deficient patients. In three patients, smaller than normal PCR products were observed, and sequence analysis revealed the deletion of a 54-bp exon in the cDNA. Sequencing of genomic DNA from these three patients led to the identification of three novel mutations in the PCCA gene, two short deletions and one small insertion, adjacent to short direct repeats, and all of them affecting the consensus splice sites of the skipped exon. These mutations, 1771IVS-2del9, 1824IVS+3del4, and 1824IVS+3insCT, are the cause of the aberrant splicing of the PCCA pre-mRNA and result in an in-frame deletion of 54 nucleotides in the cDNA, probably leading to an unstable protein structure which is responsible for the lack of activity leading to PCC deficiency in these patients.

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The molecular defect in propionic acidemia: Exon skipping caused by an 8-bp deletion from an intron in the PCCB allele

Cited by 21 publications

References 18 publications

Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications

Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications

Detection of a normally rare transcript in propionic acidemia patients with mRNA destabilizing mutations in the PCCA gene

Three novel splice mutations in the PCCA gene causing identical exon skipping in propionic acidemia patients

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