NA12212
DNA from Fibroblast
Description:
PYRUVATE DECARBOXYLASE DEFICIENCY
PYRUVATE DEHYDROGENASE COMPLEX E1-ALPHA POLYPEPTIDE 1; PDHA1
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases |
| Class |
Disorders of Carbohydrate Metabolism |
| Quantity |
10 µg |
| Quantitation Method |
Please see our FAQ |
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Cell Type
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Fibroblast
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Transformant
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Untransformed
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Sample Source
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DNA from Fibroblast
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Relation to Proband
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proband
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Confirmation
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Clinical summary/Case history
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| PDL at Freeze |
9.83 |
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis |
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| Gene |
PDHA1 |
| Chromosomal Location |
Xp22.2-p22.1 |
| Allelic Variant 1 |
300502.0008; PYRUVATE DEHYDROGENASE E1-ALPHA DEFICIENCY |
| Identified Mutation |
ARG234GLY; Kerr et al. (1988) described 2 brothers who had deficiency of both components of E1 in liver, skeletal muscle, and heart. The pyruvate dehydrogenase complex (PDC) showed about 30% activity in kidney. The second and third components of the complex were normal. PDC activity was less than 10% of controls in lymphocytes, but normal in skin fibroblasts. Kerr et al. (1988) considered the possibility of X-linked inheritance because these patients and 4 other similarly affected patients with absence of both E1 subunits were male and because the mother, but not the father, had reduced enzyme activity in her lymphocytes. The fact that the maternal grandmother and great-grandmother had normal lymphocyte pyruvate dehydrogenase activity may indicate that the mutation had originated with the mother of the brothers. The clinical course was as severe as in the usual cases, but the neuropathologic findings of Leigh disease were not found. If the activity of pyruvate dehydrogenase had not been found to be very low in lymphocytes, the defect could easily have been overlooked because of the normal activity in fibroblasts. Wexler et al. (1992) sequenced the coding region of the alpha subunit of PDH and demonstrated a point mutation in codon 234 resulting in substitution of glycine for arginine. Study of other members of the family supported X-linked inheritance. The mutation is located in a highly conserved region of the PDHA1 gene that contains both hydrophobic and positively charged amino acid residues. Variable expression of pyruvate dehydrogenase complex deficiency in this case, with normal enzyme activity in fibroblasts, may be due to instability of the pyruvate dehydrogenase heterotetramer in specific tissues because of a disruption of subunit-subunit interaction.
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| Remarks |
PDC activity <10% of controls in lymphocytes but normal in cultured skin fibroblasts; expired at age 3; abnormal neuromuscular development and lactic acidosis; E1 component deficient in liver, skeletal muscle, and heart; similarly affected brother; passage 3 at CCR; donor subject has a hemizygous point mutation at nucleotide 832 in exon 7 of the PDHA1 gene resulting in the substitution of glycine for arginine at codon 234 [Arg234Gly (R234G)] |
| Wexler ID, Hemalatha SG, Liu TC, Berry SA, Kerr DS, Patel MS, A mutation in the E1 alpha subunit of pyruvate dehydrogenase associated with variable expression of pyruvate dehydrogenase complex deficiency. Pediatr Res32(2):169-74 1992 |
| PubMed ID: 1508605 |
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| Kerr DS, Berry SA, Lusk MM, Ho L, Patel MS, A deficiency of both subunits of pyruvate dehydrogenase which is not expressed in fibroblasts. Pediatr Res24:95-100 1988 |
| PubMed ID: 3137520 |
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