Heterogeneous Expression of Protein and mRNA in Pyruvate Dehydrogenase Deficiency (original) (raw)
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Background : Pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA which ultimately generates ATP. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits, and the resulting phenotype, though very heterogeneous, mainly affects the neuro-encephalic system. The aim of this study is to describe and discuss the clinic, metabolic and genotypic profiles of thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results : The mutational spectrum revealed that seven patients (54 %) carry mutations in the PDHA1 gene , encoding the E1α subunit, five patients (38 %) carry mutations in the PDHX gene, encoding the E3 binding protein, and the remaining patient (8 %) harbors mutations in the DLD gene, encoding the E3 subunit. These data corroborate PDHA1 mutations as the predominant cause of PDC deficiency, though revealing a notable prevalence of PDHX mutations ...
Systemic Deficiency of the First Component of the Pyruvate Dehydrogenase Complex
Pediatric Research, 1987
An infant with lactic acidosis and developmental delay had neuropathological changes consistent with Leigh's necrotizing encephalomyelopathy. Total pyruvate dehydrogenase complex (PDC) activity was low relative to controls in lymphocytes (0.2 versus 1.9 2 0.6 S D nmol/min/mg protein) and cultured skin fibroblasts (0.9 versus 2.7 + 1.0). Liver, muscle, heart, and kidney mitochondria oxidized several substrates normally, but did not oxidize pyruvate. PDC activity was absent in these mitochondria (0.1 versus 9.8 + 4.2 in liver and 0.7 versus 75 + 26 in muscle) and was very low in all tissue homogenates. Activity of the first component was low in liver mitochondria, whereas activities of the second and third components were normal. Western blot analysis of tissue proteins showed normal amounts of second and third component of PDC but undetectable to trace amounts of both a and B subunits of the first component of PDC in liver, brain, kidney, heart, and skin fibroblasts. Thus, profound systemic deficiency of PDC was due to lack of both subunit proteins of the first component of PDC.
Pyruvate dehydrogenase deficiency: Clinical and biochemical diagnosis
Pediatric Neurology, 1993
A female neonate with pyruvate dehydrogenase (PDH) deficiency is presented with clinical, radiologic, biochemical, neuropathoiogic, and molecular genetic data. She was dysmorphic, with a high forehead, lowset ears, thin upper lip, upturned nose, and rhizomelic limbs. Cranial MRI revealed severe cortical atrophy, ventricular dilatation, and corpus caliosum agenesis. Pyruvate and lactate levels were increased in CSF and blood. Urinary organic acid profile was compatible with PDH deficiency. PDH activity was normal in fibroblasts, lymphocytes, and muscle. The PDH El-or gene was sequenced and a single base mutation was found within the regulatory phosphorylation site in exon 10. It is postulated that this mutation causes a cerebral form of PDH deficiency. Tissue-specific expression of the disease could be explained by differential X chromosome inactivation because the PDH El-ct gene is located on this chromosome. Dysmorphism with severe cerebral malformations in female patients merits a metabolic evaluation, including determination of lactate and pyruvate levels in CSF.
Pyruvate dehydrogenase deficiency: Molecular basis for intrafamilial heterogeneity
Annals of Neurology, 1994
Two half-brothers and their mother had symptomatic pyruvate dehydrogenase complex deficiency. The infants had severe congenital lactic acidosis, seizures, and apneic spells and died at the ages of 3 and 4 months. The mother was less symptomatic with mental retardation, truncal ataxia, and dysarthria. The residual pyruvate dehydrogenase activities in cultured skin fibroblasts from the 2 infants and their mother were 7, 15, and 10% of control values. Immunoblot analysis showed negligible amounts of E1α and E1β subunits of the complex. Northern blot analysis for the E1α subunit showed normal results. In the 2 sons, complementary DNA sequence analysis reveled a cytosine to thymine mutation in exon 4, resulting in a change of arginine 127 to tryptophan in the E1α subunit. Restriction enzyme analysis of the polymerase chain reaction product representing exon 4 of the E1α gene revealed that the mother was a heterozygote. Complementary DNA restriction analysis and methylation analysis of the X chromosome DXS255 loci revealed skewed activation of the mutant allele, consistent with the deficient pyruvate dehydrogenase activity in the mother's fibroblasts. The milder maternal phenotype is consistent with variable X-inactivation patterns in different organs of female heterozygotes.
Orphanet Journal of Rare Diseases
Background The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype–phenotype correlations. Results The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1α subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, m...
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2002
Genetic defects in pyruvate dehydrogenase complex (PDC) cause lactic acidosis, neurological deficits, and often early death. Most mutations of PDC are localized in the K subunit of the pyruvate dehydrogenase (E1) component. We have kinetically characterized a patient's missense mutation KH44R in E1K by creating and purifying three recombinant human E1s (KH44R, KH44Q, and KH44A). Substitutions at histidine-15 resulted in decreased V max values (6% KH44R ; 30% KH44Q ; 90% KH44A) while increasing K m values for thiamine pyrophosphate (TPP) compared to wild-type (KH44R, 3-fold; KH44Q, 7-fold ; KH44A, 10-fold). This suggests that the volume of the residue at site 15 is important for TPP binding and substitution by a residue with a longer side chain disrupts the active site more than the TPP binding site. The rates of phosphorylation and dephosphorylation of KH44R E1 by E1-kinase and phospho-E1 phosphatase, respectively, were similar to that of the wild-type E1 protein. These results provide a biochemical basis for altered E1 function in the KH44R E1 patient. ß 2002 Elsevier Science B.V. All rights reserved.
Prague medical report, 2011
The most common cause of pyruvate dehydrogenase complex (PDHc) deficiency is the deficit of the E1α-subunit. The aim of this study was to describe distinct course of the disease in two boys with mutations in PDHA1 gene and illustrate the possible obstacles in measurement of PDHc activity. Clinical data and metabolic profiles were collected and evaluated. PDHc and E1α-subunit activities were measured using radiometric assay. Subunits of PDHc were detected by Western blot. PDHA1 gene was analysed by direct sequencing. In patient 1, the initial hypotonia with psychomotor retardation was observed since early infancy. The child gradually showed symptoms of spasticity and arrest of psychomotor development. In patient 2, the disease manifested by seizures and hyporeflexia in the toddler age. The diagnosis was confirmed at the age of seven years after attacks of dystonia and clinical manifestation of myopathy with normal mental development.
Pyruvate dehydrogenase deficiency: The relation of the E1α mutation to the E1β subunit deficiency
Pediatric Neurology, 1996
We report 7 patients with pyruvate dehydrogenase (PDH) deficiency caused by mutations of the PDH-Elc~ subunit. Each patient had a different mutation; 4 with duplicate insertions, 1 with a deletion of tandem repeat, and 2 with point mutations. Five of the mutations were novel, thus confirming ailelic heterogeneity. Immunobiot analysis revealed decreased immunoreactivity for the Elan and Eli3 subunits in every patient. Pulse-labeling and chase study for the Elcll and Eli3 subunits revealed that initial synthesis of the mutant Elc~ subunit was normal and posttransiationai degradation was complete by 48 hours. However, the posttranslational degradation rate of the ElR subunit varied from one patient to another. Factors other than instability of the ElR monomer must contribute to the degradation rate of this subunit in the presence of an Elcll subunit mutation. Including this series, 3 patients with the S312 deletion and 5 with the R302C point mutation have been reported, and all of these patients are female. These findings suggest that these two loci are hot spots for gene mutations, and may be lethal in the male fetus.
JIMD Reports
Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fluoride) PDC activities in lymphocytes and fibroblasts, normal activity of other mitochondrial enzymes in fibroblasts, and novel biallelic frameshift mutation in the PDP1 gene, c.575dupT (p.L192FfsX5), with absent PDP1 product in fibroblasts. Unexpectedly, the patient also had low branched-chain 2-ketoacid dehydrogenase (BCKDH) activity in fibroblasts with slight elevation of branched-chain amino acids in plasma and ketoacids in urine but with no pathogenic mutations in the enzymes of BCKDH, which could suggest shared regulatory function of PDC and BCKDH in fibroblasts, potentially in other tissues or cell types as well, but this remains to be determined.