Mutations in the X-linked pyruvate dehydrogenase (E1) ? subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency

Lissens, Willy; Meırleır, Linda De; Seneca, Sara; Liebaers, Inge; Brown, Garry K.; Brown, Ruth; M, Ito; Naito, Etsuo; Kuroda, Yasuhiro; Kerr, Douglas S.; Wexler, Isaiah D.; Patel, Mulchand S.; Robinson, Brian H.; Seyda, Agnieszka

doi:10.1002/(sici)1098-1004(200003)15:3<209::aid-humu1>3.0.co;2-k

Cited by 197 publications

(135 citation statements)

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“…None of the mutations that have been well defined as causing "thiamine-responsive" PDHC deficiency have involved amino acid residues that are directly involved in TPP binding; most are adjacent to the binding site and probably alter the position of the actual side chains that interact with the cofactor, weakening their binding. There are two groups of these: p. Ile87Met (present report), p.Arg88Ser (Marsac et al 1997), p.Arg88Cys (Fujii et al 2006) and p.Gly89Ser (Naito et al 1999) on one side and p.Phe205Leu (Naito et al 2002a), p.Met210Val (Tripatara et al 1999), p.Trp214 (Lissens et al 2000), p.Leu216Phe (Naito et al 2002a) and p. Pro217Leu (also denoted as Pro188Leu) (Hemalatha et al 1995) on the other. A number of patients have been reported as thiamine responsive but have mutations involving amino acid residues that are located well away from the TPP-binding site.…”

Section: Discussionmentioning

confidence: 56%

“…Four main neurological presentations have been reported: neonatal encephalopathy with lactic acidosis, non-progressive infantile encephalopathy, Leigh syndrome and relapsing ataxia (Robinson et al 1987;Brown et al 1988Brown et al , 1989aBarnerias et al 2010;Patel et al 2012). The majority of patients have a mutation located in the PDHA1 gene encoding the E1a subunit, which is located on the X chromosome (Robinson and Sherwood 1984;McKay et al 1986;Wicking et al 1986;Brown et al 1989b;Lissens et al 2000). The differences in presentation result from variations in mutations and from the degree of X inactivation in females (Brown et al 1989b;Dahl et al 1992).…”

Section: Introductionmentioning

confidence: 99%

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Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment

Dongen

Brown

et al. 2014

JIMD Reports

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment

Dongen

Brown

et al. 2014

JIMD Reports

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“…The E1 enzyme is a heterotetramer of two E1 ␣ subunits (PDHA1) and two E1 ␤ subunits (PDHB) with thiamine pyrophosphate as a cofactor for pyruvate decarboxylation. Mutations in this complex are the major cause of primary lactic acidosis, which is complicated by neurological presentations due to degenerative changes in the central nervous system where high energy from the aerobic oxidation of glucose is indispensable (28,29).…”

Section: Discussionmentioning

confidence: 99%

ATP6AP2/(Pro)renin Receptor Contributes to Glucose Metabolism via Stabilizing the Pyruvate Dehydrogenase E1 β Subunit

Kanda

Noda

Ishida

2015

Journal of Biological Chemistry

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Background:The mechanism of efficient energy generation in the highly evolved mammalian retina remains incompletely understood. Results: ATP6PA2 interacts with the E1 ␤ subunit of pyruvate dehydrogenase, a key enzyme in aerobic energy generation, controlling its protein stability. Conclusion: ATP6AP2 contributes to glucose metabolism together with oxidative stress. Significance: The present data provide a novel insight into the biological function of ATP6AP2 in the retina.

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“…By far the majority of biochemically proven cases of PDH deficiency are due to defects in the E1α subunit. Mutations in the X-linked E1α subunit gene (PDHA1) may give rise to diminished enzyme catalytic activity with or without reduction in E1α mRNA and/or protein [5,6]. There are no proven treatments for PDH complex deficiency.…”

Section: Introductionmentioning

confidence: 99%

A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate

Han

Berendzen

Zhong

et al. 2008

Molecular Genetics and Metabolism

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We determined the ability of self-complementary adeno-associated virus (scAAV) vectors to deliver and express the pyruvate dehy-drogenase E1α subunit gene (PDHA1) in primary cultures of skin fibroblasts from 3 patients with defined mutations in PHDA1 and 3 healthy subjects. Cells were transduced with scAAV vectors containing the cytomegalovirus promoter-driven enhanced green fluorescent protein (EGFP) reporter gene at a vector:cell ratio of 200. Transgene expression was measured 72 h later. The transduction efficiency of scAAV2 and scAAV6 vectors was 3-to 5-fold higher than that of the other serotypes, which were subsequently used to transduce fibroblasts with wild-type PDHA1 cDNA under the control of the chicken beta-action (CBA) promoter at a vector:cell ratio of 1000. Total PDH-specific activity and E1α protein expression were determined 10 days posttransduction. Both vectors increased E1α expression 40-60% in both control and patient cells, and increased PDH activity in two patient cell lines. We also used dichloroacetate (DCA) to maximally activate PDH through dephosphorylation of E1α. Exposure for 24 h to 5 mM DCA increased PDH activity in non-transduced control (mean 37% increase) and PDH deficient (mean 44% increase) cells. Exposure of transduced patient fibroblasts to DCA increased PDH activity up to 90% of the We have proposed that the PDH complex, specifically the E1α subunit, should be considered an important target for gene therapy of mitochondrial energy failure [10]. As proof of concept, we demonstrated that recombinant adeno-associated virus (AAV) could be used to package gene targeting vectors as single-strand molecules carrying the wild-type PDHA1 cDNA, deliver the vector to cultured mammalian cells [11] and partially restore PDH activity in a primary culture of skin fibroblasts from a patient with E1α deficiency [12]. However the efficiency of transgene expression was low (~25% of cells) due to the single-stranded nature of the recombinant vector genome. Moreover, only one AAV serotype was evaluated (AAV2) and the findings were limited to cells from a single patient.Therefore, to optimize the delivery and expression of PDHA1, we employed here doublestranded DNA-containing self-complementary AAV (scAAV) vectors that by-pass the requirement of viral second-strand DNA synthesis. We then investigated the relative transduction efficiency of several scAAV-enhanced green fluorescent protein (EGFP) serotype vectors in both normal and E1α-deficient cultured fibroblasts. Finally, we determined the effectiveness of scAAV-mediated gene transfer alone and combined with DCA to restore PDH activity in defective cells. Materials and methods Cell culture, treatment and plasmidsPrimary cultures of fibroblasts were established from skin biopsies of three healthy subjects and three patients (one male and two females) with PDH E1α deficiency. The patients had the following mutations in the PDHA1 gene: patient 1, c.1163_1166dupAAGT in exon 11; patient 2, c.904C>T in exon 10; and patient 3, c.642G>T in exon...

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Mutations in the X-linked pyruvate dehydrogenase (E1) ? subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency

Cited by 197 publications

References 58 publications

Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment

Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment

ATP6AP2/(Pro)renin Receptor Contributes to Glucose Metabolism via Stabilizing the Pyruvate Dehydrogenase E1 β Subunit

A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate

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