title: Complex genetic findings in a female patient with pyruvate dehydrogenase complex deficiency: Null mutations in the PDHX gene associated with unusual expression of the testis-specific PDHA2 gene in her somatic cells.
abstract: Human pyruvate dehydrogenase complex (PDC) catalyzes a key step in the generation of cellular energy and is composed by three catalytic elements (E1, E2, E3), one structural subunit (E3-binding protein), and specific regulatory elements, phosphatases and kinases (PDKs, PDPs). The E1α subunit exists as two isoforms encoded by different genes: PDHA1 located on Xp22.1 and expressed in somatic tissues, and the intronless PDHA2 located on chromosome 4 and only detected in human spermatocytes and spermatids. We report on a young adult female patient who has PDC deficiency associated with a compound heterozygosity in PDHX encoding the E3-binding protein. Additionally, in the patient and in all members of her immediate family, a full-length testis-specific PDHA2 mRNA and a 5'UTR-truncated PDHA1 mRNA were detected in circulating lymphocytes and cultured fibroblasts, being both mRNAs translated into full-length PDHA2 and PDHA1 proteins, resulting in the co-existence of both PDHA isoforms in somatic cells. Moreover, we observed that DNA hypomethylation of a CpG island in the coding region of PDHA2 gene is associated with the somatic activation of this gene transcription in these individuals. This study represents the first natural model of the de-repression of the testis-specific PDHA2 gene in human somatic cells, and raises some questions related to the somatic activation of this gene as a potential therapeutic approach for most forms of PDC deficiency.
authors.affiliation: Metabolism & Genetics Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Pinheiro
authors.affiliation: Metabolism & Genetics Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Silva
authors.affiliation: Metabolism & Genetics Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors.forename: Hana
authors.initials: H
authors.lastname: Pavlu-Pereira
authors.affiliation: Metabolism & Genetics Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Florindo
authors.affiliation: Metabolism & Genetics Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors.forename: Madalena
authors.initials: M
authors.lastname: Barroso
authors.affiliation: Department of Human Genetics, Molecular Cytogenetic Unit, National Institute of Health Doctor Ricardo Jorge, I.P., Lisbon, Portugal.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Marques
authors.affiliation: Department of Human Genetics, Molecular Cytogenetic Unit, National Institute of Health Doctor Ricardo Jorge, I.P., Lisbon, Portugal.
authors.forename: Hildeberto
authors.initials: H
authors.lastname: Correia
authors.affiliation: Department of Medicine, Hospital Santa Maria, Lisbon, Portugal.
authors.forename: Anabela
authors.initials: A
authors.lastname: Oliveira
authors.affiliation: Department of Pediatrics, Hospital Santa Maria, Lisbon, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Gaspar
authors.affiliation: Metabolism & Genetics Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Tavares de Almeida
authors.affiliation: Metabolism & Genetics Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Portugal. Electronic address: iarivera@ff.ulisboa.pt.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rivera
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D018628:Gene Dosage; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000235:genetics*; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics* / Q000378:metabolism; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000235:genetics*; D012333:RNA, Messenger; D013737:Testis / Q000378:metabolism
chemical_list: C045867:PDHX protein, human; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; C550671:PDHA2 protein, human; D030481:Pyruvate Dehydrogenase (Lipoamide)
keywords: DNA methylation; Gene regulation; Pyruvate dehydrogenase complex deficiency; Testis- specific expression