Propionic acidemia: identification of twenty-four novel mutations in Europe and North America

Pérez, Belén; Desviat, Lourdes R.; Rodríguez‐Pombo, Pilar; Clavero, Sonia; Navarrete, Rosa; Pérez‐Cerdá, Celia; Ugarte, Magdalena

doi:10.1016/s1096-7192(02)00197-x

Cited by 60 publications

(39 citation statements)

References 31 publications

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“…With the sequence information available, it has been possible to identify mutations from propionic acidemia patients (8 -10), and many new mutations have been found recently in different ethnic groups (11,12). Currently, ϳ52 and 53 mutations have been reported in the PCCA and PCCB genes, respectively (for a continuously updated list of all reported PCC mutations see uchsc.edu/cbs/ pcc/pccmain.htm).…”

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confidence: 99%

Characterization of Four Variant Forms of Human Propionyl-CoA Carboxylase Expressed in Escherichia coli

Jiang

Rao

Yee

et al. 2005

Journal of Biological Chemistry

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Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, ␣ PCC and ␤ PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. Deficiency of PCC results in a metabolic disorder, propionic acidemia, which is sufficiently severe to cause neonatal death. We have purified three PCCs containing pathogenic mutations in the ␤ subunit (R165W, E168K, and R410W) and one PCCB polymorphism (A497V) to homogeneity to elucidate the potential structural and functional effects of these substitutions. We observed no significant difference in K m values for propionyl-CoA between wild-type and the variant enzymes, which indicated that these substitutions had no effect on the affinity of the enzyme for this substrate. Furthermore, the kinetic studies indicated that mutation R410W was not involved in propionyl-CoA binding in contrast to a previous report. The three mutant PCCs had half the catalytic efficiency of wild-type PCC as judged by the k cat /K m ratios. No significant differences have been observed in molecular mass or secondary structure among these enzymes. However, the variant PCCs were less thermostable than the wild-type. Following incubation at 47°C, blue native-PAGE revealed a lower oligomeric form (␣ 2 ␤ 2 ) in the three mutants not detectable in wildtype and the polymorphism. Interestingly, the lower oligomeric form was also observed in the corresponding crude Escherichia coli extracts. Our biochemical data and the structural analysis using a ␤ PCC homology model indicate that the pathogenic nature of these mutations is more likely to be due to a lack of assembly rather than disruption of catalysis. The strong favorable effect of the co-expressed chaperone proteins on PCC folding, assembly, and activity suggest that propionic acidemia may be amenable to chaperone therapy.Four different biotin-dependent carboxylases are known to play a central role in mammalian metabolic pathways, such as oxidation of odd-chain fatty acids, catabolism of branched amino acids, fatty acid synthesis, and gluconeogenesis. One of these is propionyl-CoA carboxylase (PCC, 1 EC 6.4.1.3), which catalyzes the conversion of propionyl-CoA to D-methylmalonylCoA in the mitochondrial matrix (1). This enzyme consists of two nonidentical subunits, ␣ and ␤, encoded by two different nuclear genes, designated PCCA and PCCB, respectively. Structural studies of the human enzyme have indicated that ␣ PCC is 72 kDa in size, whereas ␤ PCC is 54 kDa. Overall, PCC has an ␣ 6 ␤ 6 structure (1, 2). Mutations in either gene result in an autosomal recessive disease, propionic acidemia (MIM 606054), which usually presents as a life-threatening ketoacidosis in the neonatal period with protein intolerance, vomiting, failure to thrive, lethargy, and profound metabolic acidosis symptoms. This disease can result in mental retardation and can be sufficiently severe to cause neonatal death (1).The cDNAs for ␣ and ␤ subunits hav...

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confidence: 99%

Characterization of Four Variant Forms of Human Propionyl-CoA Carboxylase Expressed in Escherichia coli

Jiang

Rao

Yee

et al. 2005

Journal of Biological Chemistry

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“…Apart from repeated isolated elevations in C3 on plasma acylcarnitine analysis and mild elevations of glycine, she shows no biochemical evidence of propionic acidemia with no detectable analytes suggestive of PA in repeated qualitative urine organic acid analyses. Sanger sequencing identified compound heterozygous pathogenic mutations in the PCCA gene in transconfiguration: c.223G>C (p. A75P) and c.923dupT (p. L308FfsX35) that have been previously identified and characterized (Campeau et al 1999;Pérez et al 2003;Yang et al 2004). No mutations were identified in PCCB.…”

Section: Patientmentioning

confidence: 95%

“…Molecular testing confirmed the diagnosis of PA by finding two heterozygous bi-allelic variants, c.562G>A (p. G188R) and c.1127G>A (p. R376H), in PCCB gene. The first mutation was previously reported (Pérez et al 2003), while the second variant is a novel mutation predicted to be pathogenic (Table 2). At 20 months of age, there were no growth concerns, and he was developmentally normal (walking and two words sentences).…”

Section: Patientmentioning

confidence: 97%

Expansion of the Phenotypic Spectrum of Propionic Acidemia with Isolated Elevated Propionylcarnitine

et al. 2016

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We report three patients with elevations of propionylcarnitine (C3), one without elevations of 2-methylcitrate and 3-hydroxypropionate in urine organic acid analysis, and the other two showing only mild elevations, all of whom were subsequently confirmed to have propionic acidemia by molecular analysis of PCCA and PCCB genes. To date, they have had a mild clinical course. These cases illustrate the importance of considering high C3 as the only biochemical abnormality in a diagnosis of propionic acidemia. Since mild C3 elevations may be overlooked and considered non-diagnostic in isolation, we advise considering a diagnosis of propionic acidemia even in the absence of significant elevations 2-methylcitrate or 3-hydroxypropionate in urine organic acid analysis.Abbreviations 2-MCA 2-Methylcitrate 3-OHP 3-Hydroxypropionate C3 Propionylcarnitine

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“…Propionic acidemia (PA, OMIM #606054) is a rare [1] autosomal recessive genetic disease [2] resulting from propionylcoenzyme A (CoA) carboxylase deficiency [3]. This mitochondrial enzyme is essential near the end of the catabolic pathway to metabolize leucine, isoleucine, valine, threonine, methionine [3][4][5][6] and 3-carbon fatty acids [2].…”

Section: Introductionmentioning

confidence: 99%

“…This mitochondrial enzyme is essential near the end of the catabolic pathway to metabolize leucine, isoleucine, valine, threonine, methionine [3][4][5][6] and 3-carbon fatty acids [2].…”

Section: Introductionmentioning

confidence: 99%

Propionic Academia: Exome Sequencing Identified Novel Mutation in Exon 12 of PCCA Gene

Khalesi¹,

Garshasbi²

2017

J Med Cases

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Propionic acidemia (PA) is a rare autosomal recessive genetic disorder resulting from propionyl-coenzyme A carboxylase deficiency. This mitochondrial enzyme is a heterocopolymer of two subunits a and b that are encoded by PCCA and PCCB genes, respectively. The phenotypes of PCCA mutations are most varied ranging from mild to lethal within a few days after birth because there is great heterogeneity in the mutations of PCCA, while PCCB bears only a limited number of mutations. Deep resequencing of all human genes could potentially identify allelic variants involved in a given rare monogenic disease. Whole exome sequencing (WES) is well justified as an efficient strategy to search for mutations in rare Mendelian disorders. Here, we analyzed an Iranian couple with the history of having a child who died probably due to PA by WES. We could report a novel heterozygous non-sense mutation (p.Y380X) in exon 12 of the PCCA gene, resulting in the protein truncation. We could find that both of parents are carrier for a heterozygous novel non-sense mutation in PCCA gene. We showed that WES in parents, along with appropriate filtering against public SNP databases, is sufficient to identify carriers for a known monogenic disorder, PA, in a consanguineous family.

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Propionic acidemia: identification of twenty-four novel mutations in Europe and North America

Cited by 60 publications

References 31 publications

Characterization of Four Variant Forms of Human Propionyl-CoA Carboxylase Expressed in Escherichia coli

Characterization of Four Variant Forms of Human Propionyl-CoA Carboxylase Expressed in Escherichia coli

Expansion of the Phenotypic Spectrum of Propionic Acidemia with Isolated Elevated Propionylcarnitine

Propionic Academia: Exome Sequencing Identified Novel Mutation in Exon 12 of PCCA Gene

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