Propionic acidemia: mutation update and functional and structural effects of the variant alleles

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

doi:10.1016/j.ymgme.2004.08.001

Cited by 77 publications

(80 citation statements)

References 50 publications

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“…Intron 3 is small, 104 bp, and the splice sites of exon 4 are weak, probably determining that both exons 3 and 4 are skipped together as a consequence of the mutation. Skipping of both exons in cDNA has also been observed in other patients, as in 19218 included in this study, with a yet unidentified causative mutation in genomic DNA (Desviat et al 2004).…”

Section: Resultssupporting

confidence: 71%

“…At the cDNA level, the skipping of exon 13 is observed, which predictably originates a protein with an internal deletion of 48 amino acids. This change has been detected in two patients of Turkish origin (one homozygous and one heterozygous) and in one homozygous (Desviat et al 2004) Afghan patient, the latter being up to date asymptomatic after being detected in a neonatal tandem mass screening program. The Shapiro score for the normal donor splice site of exon 13 is 79.4, whereas it decreases to 76.1 with the mutation.…”

Section: Resultsmentioning

confidence: 94%

“…PA is highly heterogeneous at the genetic level, especially for Caucasian PCCA-deficient patients with no prevalent mutations, while for the PCCB gene a limited number of mutations accounts for most of the mutant alleles. A mutation update and review of the expression analysis of PCCA and PCCB mutations has been published recently (Desviat et al 2004). In both genes, missense mutations are the most frequent defects (approximately 40%) followed by small insertions/deletions and splicing mutations, most of which result in frameshift.…”

Section: Introductionmentioning

confidence: 99%

“…The mutational spectrum is clearly population specific. Several Caucasian and Oriental populations have been genetically analyzed, and some mutations have been found to be exclusively associated with geographical or ethnic groups (PCCB mutations E168K in Spanish chromosomes, A513_R514insP in the Inuit population, T428I in Orientals, etc) (Desviat et al 2004).…”

Section: Introductionmentioning

confidence: 99%

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New splicing mutations in propionic acidemia

et al. 2006

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Propionic acidemia results from mutations in either of the two genes, PCCA or PCCB, that encode the two subunits of the propionyl-CoA carboxylase (PCC) enzyme. In this study, we report the identification and analysis of seven novel splicing mutations involving consensus donor and acceptor splice sites. Most of them were identified in patients with a Central Asian origin, and some present in several alleles, probably reflecting founder effects. The functional consequences of the splicing mutations were analyzed in patients' fibroblasts, as well as transcript quantification using real-time PCR methods. In the PCCA gene, two mutations were demonstrated to affect 5¢ splice sites (c.231+1G>C and c.1209+3A>G) and two 3¢ acceptor splice sites (c.1210delG and c.1430G>T), all causing skipping of the exons involved, with no detectable levels of normally spliced transcript. In the PCCB gene, all three mutations involved 5¢ donor splice sites-two affected exon 1 splicing (c.154_183+17del46 and c.183+2T>C), the latter activating a cryptic splice site in intron 1, and the remaining mutation (c.1498+2T>C) resulted in exon 14 skipping. The results highlight the necessity to perform transcript analysis in addition to genomic DNA sequencing to characterize the effect of splicing mutations and add relevant information on the genetic epidemiology of the disease.

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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New splicing mutations in propionic acidemia

et al. 2006

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“…This A138T PCCA protein with reduced activity was identified in PA patients with a mild form of the disease (Ugarte et al, 1999;Perez-Cerda et al, 2000;Desviat et al, 2004). Pcca -/ -(A138T) mice survive to adulthood, but have significant elevations of circulating C3, MeCit, glycine, and ammonia along with cardiac defects consistent with PA (Guenzel et al, 2013).…”

Section: Introductionmentioning

confidence: 98%

Effects of Adeno-Associated Virus Serotype and Tissue-Specific Expression on Circulating Biomarkers of Propionic Acidemia

et al. 2014

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Propionic acidemia (PA) is an autosomal recessive inborn error of metabolism caused by deficiency of propionyl-CoA carboxylase (PCC). This enzyme is composed of six PCCA and six PCCB subunits and mediates a critical step in catabolism of odd chain fatty acids and certain amino acids. Current treatment options for PA are limited to stringent dietary restriction of protein consumption and some patients undergo elective liver transplantation. We previously generated a hypomorphic model of PA, designated Pcca

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Methylmalonic and propionic aciduria

Deodato

Boenzi

Santorelli

et al. 2006

American J of Med Genetics Pt C

234

186

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Methylmalonic and propionic aciduria (PA) are the most frequent forms of branched-chain organic acidurias. These autosomal recessive disorders result from deficient activity of methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. Clinically, acute or chronic neurologic signs are caused by the accumulation of toxic compounds proximal to the metabolic block. Phenotype varies from severe neonatal-onset forms with high mortality and poor outcome to milder forms with a later onset. In both cases the clinical course is dominated by the risk of relapses of life-threatening episodes of metabolic decompensation and of severe organ failure. Despite improvement of treatment, the overall outcome remains disappointing with no major differences between the two diseases. The diagnosis is based on the presence of characteristic compounds in body fluids as detected by organic acid analysis in urine and acylcarnitine profile in blood. Therapy is based on low-protein high-energy diet, carnitine supplementation, and metronidazole. Some patients with methylmalonic aciduria (MMA) respond to pharmacological doses of vitamin B12. Given the poor long-term prognosis, liver transplantation has been recently attempted as an alternative therapy to conventional medical treatment to cure the underlying metabolic defect. Nevertheless, the overall experience to date does not clearly demonstrate its effectiveness in preventing further deterioration or improving survival and quality of life. The recent implementation of neonatal screening by electrospray tandem mass spectrometry has decreased early mortality and improved the short-term outcome, without changing the detection rate of both diseases in the screening population compared to clinically detected cases. However, the limited number of patients and the short duration of their follow-up do not yet permit drawing final conclusions on its effect on the long-term outcome of methylmalonic and propionic acidemia.

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Propionic acidemia: mutation update and functional and structural effects of the variant alleles

Cited by 77 publications

References 50 publications

New splicing mutations in propionic acidemia

New splicing mutations in propionic acidemia

Effects of Adeno-Associated Virus Serotype and Tissue-Specific Expression on Circulating Biomarkers of Propionic Acidemia

Methylmalonic and propionic aciduria

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