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[PMID]:28838934
[Au] Autor:Feingold B; Mahle WT; Auerbach S; Clemens P; Domenighetti AA; Jefferies JL; Judge DP; Lal AK; Markham LW; Parks WJ; Tsuda T; Wang PJ; Yoo SJ; American Heart Association Pediatric Heart Failure Committee of the Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Stroke Council
[Ti] Título:Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association.
[So] Source:Circulation;136(13):e200-e231, 2017 Sep 26.
[Is] ISSN:1524-4539
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.
[Mh] Termos MeSH primário: Cardiomiopatias/diagnóstico
Doenças Musculares/diagnóstico
Doenças Neuromusculares/diagnóstico
[Mh] Termos MeSH secundário: American Heart Association
Síndrome de Barth/diagnóstico
Síndrome de Barth/genética
Síndrome de Barth/metabolismo
Síndrome de Barth/patologia
Cardiomiopatias/complicações
Cardiomiopatias/patologia
Ataxia de Friedreich/diagnóstico
Ataxia de Friedreich/metabolismo
Ataxia de Friedreich/patologia
Seres Humanos
Doenças Musculares/metabolismo
Doenças Musculares/patologia
Distrofia Muscular do Cíngulo dos Membros/diagnóstico
Distrofia Muscular do Cíngulo dos Membros/metabolismo
Distrofia Muscular do Cíngulo dos Membros/patologia
Distrofia Muscular de Duchenne/diagnóstico
Distrofia Muscular de Duchenne/metabolismo
Distrofia Muscular de Duchenne/patologia
Distrofia Muscular de Emery-Dreifuss/diagnóstico
Distrofia Muscular de Emery-Dreifuss/metabolismo
Distrofia Muscular de Emery-Dreifuss/patologia
Miopatias Congênitas Estruturais/diagnóstico
Miopatias Congênitas Estruturais/genética
Miopatias Congênitas Estruturais/metabolismo
Miopatias Congênitas Estruturais/patologia
Distrofia Miotônica/diagnóstico
Distrofia Miotônica/metabolismo
Distrofia Miotônica/patologia
Doenças Neuromusculares/complicações
Doenças Neuromusculares/patologia
Fatores de Risco
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; PRACTICE GUIDELINE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170826
[St] Status:MEDLINE
[do] DOI:10.1161/CIR.0000000000000526


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[PMID]:28108107
[Au] Autor:Woiewodski L; Ezon D; Cooper J; Feingold B
[Ad] Endereço:Geisinger Commonwealth School of Medicine, Scranton, PA.
[Ti] Título:Barth Syndrome with Late-Onset Cardiomyopathy: A Missed Opportunity for Diagnosis.
[So] Source:J Pediatr;183:196-198, 2017 Apr.
[Is] ISSN:1097-6833
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A male infant presented with neutropenia, growth delay, and death of a maternal uncle at age 2 years. Despite extensive evaluation over 10 years, Barth syndrome was not diagnosed until he presented in acute heart failure. Although late-onset cardiomyopathy is rare, persistence of common Barth features should have enabled earlier diagnosis.
[Mh] Termos MeSH primário: Síndrome de Barth/diagnóstico
Cardiomiopatia Dilatada/diagnóstico
Diagnóstico Tardio
Insuficiência Cardíaca/diagnóstico
Neutropenia/diagnóstico
[Mh] Termos MeSH secundário: Síndrome de Barth/terapia
Cardiomiopatia Dilatada/terapia
Seguimentos
Insuficiência Cardíaca/terapia
Seres Humanos
Masculino
Neutropenia/terapia
Doenças Raras
Medição de Risco
Fatores de Tempo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170122
[St] Status:MEDLINE


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[PMID]:28097490
[Au] Autor:Mejia EM; Zinko JC; Hauff KD; Xu FY; Ravandi A; Hatch GM
[Ad] Endereço:Department of Pharmacology and Therapeutics, Faculty of Health Sciences, University of Manitoba, 753 McDermot Avenue, Winnipeg, MB, R3E 0W3, Canada.
[Ti] Título:Glucose Uptake and Triacylglycerol Synthesis Are Increased in Barth Syndrome Lymphoblasts.
[So] Source:Lipids;52(2):161-165, 2017 Feb.
[Is] ISSN:1558-9307
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Barth syndrome (BTHS) is an X-linked genetic disease resulting in loss of cardiolipin (Ptd Gro). Patients may be predisposed to hypoglycemia and exhibit increases in whole-body glucose disposal rates and a higher fat mass percentage. We examined the reasons for this in BTHS lymphoblasts. BTHS lymphoblasts exhibited a 60% increase (p < 0.004) in 2-[1,2- H(N)]deoxy-D-glucose uptake, a 40% increase (p < 0.01) in glucose transporter-3 protein expression, an increase in phosphorylated-adenosine monophosphate kinase (AMPK) and a 58% increase (p < 0.001) in the phosphorylated-AMPK/AMPK ratio compared to controls. In addition, BTHS lymphoblasts exhibited a 90% (p < 0.001) increase in D-[U- C]glucose incorporated into 1,2,3-triacyl-sn-glycerol (TAG) and a 29% increase (p < 0.025) in 1,2-diacyl-sn-glycerol acyltransferase-2 activity compared to controls. Thus, BTHS lymphoblasts exhibit increased glucose transport and increased glucose utilization for TAG synthesis. These results may, in part, explain why BTHS patients exhibit an increase in whole-body glucose disposal rates, may be predisposed to hypoglycemia and exhibit a higher fat mass percentage.
[Mh] Termos MeSH primário: Síndrome de Barth/metabolismo
Glucose/metabolismo
Linfócitos/citologia
Triglicerídeos/metabolismo
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo
Células Cultivadas
Criança
Pré-Escolar
Transportador de Glucose Tipo 3/metabolismo
Seres Humanos
Ativação Linfocitária
Linfócitos/metabolismo
Masculino
Fosforilação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glucose Transporter Type 3); 0 (SLC2A3 protein, human); 0 (Triglycerides); EC 2.7.11.31 (AMP-Activated Protein Kinases); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170119
[St] Status:MEDLINE
[do] DOI:10.1007/s11745-017-4232-7


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[PMID]:28070695
[Au] Autor:Ikon N; Ryan RO
[Ad] Endereço:Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA, 94609, USA.
[Ti] Título:Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy.
[So] Source:Lipids;52(2):99-108, 2017 Feb.
[Is] ISSN:1558-9307
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The Barth syndrome (BTHS) is caused by an inborn error of metabolism that manifests characteristic phenotypic features including altered mitochondrial membrane phospholipids, lactic acidosis, organic acid-uria, skeletal muscle weakness and cardiomyopathy. The underlying cause of BTHS has been definitively traced to mutations in the tafazzin (TAZ) gene locus on chromosome X. TAZ encodes a phospholipid transacylase that promotes cardiolipin acyl chain remodeling. Absence of tafazzin activity results in cardiolipin molecular species heterogeneity, increased levels of monolysocardiolipin and lower cardiolipin abundance. In skeletal muscle and cardiac tissue mitochondria these alterations in cardiolipin perturb the inner membrane, compromising electron transport chain function and aerobic respiration. Decreased electron flow from fuel metabolism via NADH ubiquinone oxidoreductase activity leads to a buildup of NADH in the matrix space and product inhibition of key TCA cycle enzymes. As TCA cycle activity slows pyruvate generated by glycolysis is diverted to lactic acid. In turn, Cori cycle activity increases to supply muscle with glucose for continued ATP production. Acetyl CoA that is unable to enter the TCA cycle is diverted to organic acid waste products that are excreted in urine. Overall, reduced ATP production efficiency in BTHS is exacerbated under conditions of increased energy demand. Prolonged deficiency in ATP production capacity underlies cell and tissue pathology that ultimately is manifest as dilated cardiomyopathy.
[Mh] Termos MeSH primário: Síndrome de Barth/metabolismo
Cardiolipinas/metabolismo
Miocárdio/metabolismo
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Síndrome de Barth/genética
Síndrome de Barth/fisiopatologia
Transporte de Elétrons
Seres Humanos
Mitocôndrias/metabolismo
Mutação
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cardiolipins); 0 (TAZ protein, human); 0 (Transcription Factors); 8L70Q75FXE (Adenosine Triphosphate)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170720
[Lr] Data última revisão:
170720
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170111
[St] Status:MEDLINE
[do] DOI:10.1007/s11745-016-4229-7


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[PMID]:27434059
[Au] Autor:Aryal B; Rao VA
[Ad] Endereço:Laboratory of Applied Biochemistry, Division of Biotechnology Review and Research III, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, United States of America.
[Ti] Título:Deficiency in Cardiolipin Reduces Doxorubicin-Induced Oxidative Stress and Mitochondrial Damage in Human B-Lymphocytes.
[So] Source:PLoS One;11(7):e0158376, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cardiolipin (CL) is an inner mitochondrial membrane phospholipid which plays an important role in mitochondrial function. Perturbation in CL biosynthesis alters mitochondrial bioenergetics causing a severe genetic disorder commonly known as Barth syndrome. Barth syndrome patients are known to have a reduced concentration and altered composition of CL. Cardiolipin is also known to have a high affinity for the chemotherapeutic agent doxorubicin (Dox), resulting in an extensive mitochondrial accumulation of the drug. Our results indicate that B-lymphocytes from healthy individuals are more sensitive to Dox-induced oxidative stress and cellular toxicity compared to the B-lymphocytes from Barth syndrome as indicated by greater cell death and greater level of cleaved caspase-3 following Dox treatment. Barth lymphocytes, when compared to healthy lymphocytes, showed a greater basal level of mitochondrial reactive oxygen species (mito-ROS), yet exhibited a lower level of induced mito-ROS production in response to Dox. Significantly less ATP content and slightly greater OXPHOS protein levels were detected in healthy cells compared to Barth cells after Dox treatment. Consistent with greater mitochondrial ROS, treatment with Dox induced a higher level of lipid peroxidation and protein carbonylation in healthy lymphocytes compared to Barth lymphocytes. The final remodeling of CL during CL synthesis is catalyzed by the tafazzin protein. Knockdown of tafazzin gene in H9c2 cardiomyocytes using siRNA showed decreased oxidant-induced damage, as observed in Barth lymphocytes. Our findings demonstrate that a deficiency in CL might provide a therapeutic advantage in favor of oxidant-induced anticancer activities.
[Mh] Termos MeSH primário: Antibióticos Antineoplásicos/farmacologia
Linfócitos B/efeitos dos fármacos
Cardiolipinas/metabolismo
Doxorrubicina/farmacologia
Estresse Oxidativo/efeitos dos fármacos
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Animais
Linfócitos B/metabolismo
Linfócitos B/patologia
Síndrome de Barth/metabolismo
Síndrome de Barth/patologia
Caspase 3/genética
Caspase 3/metabolismo
Morte Celular/efeitos dos fármacos
Linhagem Celular
Seres Humanos
Peroxidação de Lipídeos/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Miócitos Cardíacos/citologia
Miócitos Cardíacos/efeitos dos fármacos
Miócitos Cardíacos/metabolismo
Cultura Primária de Células
Fatores de Proteção
Carbonilação Proteica/efeitos dos fármacos
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Ratos
Fatores de Transcrição/antagonistas & inibidores
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (Cardiolipins); 0 (RNA, Small Interfering); 0 (Reactive Oxygen Species); 0 (TAZ protein, rat); 0 (Transcription Factors); 80168379AG (Doxorubicin); EC 3.4.22.- (CASP3 protein, human); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160720
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0158376


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[PMID]:27348092
[Au] Autor:Xu Y; Phoon CK; Berno B; D'Souza K; Hoedt E; Zhang G; Neubert TA; Epand RM; Ren M; Schlame M
[Ad] Endereço:Department of Anesthesiology, New York University School of Medicine, New York, New York, USA.
[Ti] Título:Loss of protein association causes cardiolipin degradation in Barth syndrome.
[So] Source:Nat Chem Biol;12(8):641-7, 2016 Aug.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cardiolipin is a specific mitochondrial phospholipid that has a high affinity for proteins and that stabilizes the assembly of supercomplexes involved in oxidative phosphorylation. We found that sequestration of cardiolipin in protein complexes is critical to protect it from degradation. The turnover of cardiolipin is slower by almost an order of magnitude than the turnover of other phospholipids. However, in subjects with Barth syndrome, cardiolipin is rapidly degraded via the intermediate monolyso-cardiolipin. Treatments that induce supercomplex assembly decrease the turnover of cardiolipin and the concentration of monolyso-cardiolipin, whereas dissociation of supercomplexes has the opposite effect. Our data suggest that cardiolipin is uniquely protected from normal lipid turnover by its association with proteins, but this association is compromised in subjects with Barth syndrome, leading cardiolipin to become unstable, which in turn causes the accumulation of monolyso-cardiolipin.
[Mh] Termos MeSH primário: Síndrome de Barth/metabolismo
Cardiolipinas/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cardiolipins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170604
[Lr] Data última revisão:
170604
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160628
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2113


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[PMID]:27124939
[Au] Autor:Brión M; de Castro López MJ; Santori M; Pérez Muñuzuri A; López Abel B; Baña Souto AM; Martínez Soto MI; Couce ML
[Ad] Endereço:From the Grupo de Xenética de Enfermidades Cardiovasculares, Instituto de Investigación Sanitaria de Santiago, Red de Investigación Cardiovascular, Fundación Pública Galega de Medicina Xenómica, SERGAS, Santiago de Compostela, Spain maria.brion@usc.es.
[Ti] Título:Prospective and Retrospective Diagnosis of Barth Syndrome Aided by Next-Generation Sequencing.
[So] Source:Am J Clin Pathol;145(4):507-13, 2016 Apr.
[Is] ISSN:1943-7722
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: To establish a genetic and clinical diagnosis in a newborn with fetal-onset dilated cardiomyopathy using next-generation sequencing technologies. METHODS: We have conducted the clinical evaluation of the proband and the molecular characterization of his disease by means of whole-exome sequencing. In addition, the clinical evaluation and subsequent genetic screening of five relatives has been performed. This comprises two males with features of left ventricular noncompaction cardiomyopathy, two females suspected of being carriers, and one pregnant female at risk of being a carrier and thereby transmitting the disease to her child. RESULTS: We have discovered a novel variant in the TAZ gene by means of whole-exome sequencing. This, together with the performance of further clinical analyses, led to an early diagnosis of Barth syndrome in the proband. The genetic screening of the subject's familial group revealed full cosegregation of the variant with another two affected males and identified several female carriers. CONCLUSIONS: The investigation for Barth syndrome must be considered in male babies and young boys with dilated cardiomyopathy and left ventricular noncompaction. Next-generation sequencing technologies provide an accurate and rapid diagnostic tool in prospectively and retrospectively identifying individuals with this Mendelian syndrome.
[Mh] Termos MeSH primário: Síndrome de Barth/diagnóstico
Síndrome de Barth/genética
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: Adulto
Pré-Escolar
Análise Mutacional de DNA/métodos
Feminino
Seres Humanos
Masculino
Linhagem
Estudos Prospectivos
Estudos Retrospectivos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; PUBLISHED ERRATUM
[Nm] Nome de substância:
0 (TAZ protein, human); 0 (Transcription Factors)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160429
[St] Status:MEDLINE
[do] DOI:10.1093/ajcp/aqw025


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[PMID]:27015085
[Au] Autor:Sandlers Y; Mercier K; Pathmasiri W; Carlson J; McRitchie S; Sumner S; Vernon HJ
[Ad] Endereço:Department of Chemistry, Cleveland State University, Cleveland, OH, United States of America.
[Ti] Título:Metabolomics Reveals New Mechanisms for Pathogenesis in Barth Syndrome and Introduces Novel Roles for Cardiolipin in Cellular Function.
[So] Source:PLoS One;11(3):e0151802, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Barth Syndrome is the only known Mendelian disorder of cardiolipin remodeling, with characteristic clinical features of cardiomyopathy, skeletal myopathy, and neutropenia. While the primary biochemical defects of reduced mature cardiolipin and increased monolysocardiolipin are well-described, much of the downstream biochemical dysregulation has not been uncovered, and biomarkers are limited. In order to further expand upon the knowledge of the biochemical abnormalities in Barth Syndrome, we analyzed metabolite profiles in plasma from a cohort of individuals with Barth Syndrome compared to age-matched controls via 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. A clear distinction between metabolite profiles of individuals with Barth Syndrome and controls was observed, and was defined by an array of metabolite classes including amino acids and lipids. Pathway analysis of these discriminating metabolites revealed involvement of mitochondrial and extra-mitochondrial biochemical pathways including: insulin regulation of fatty acid metabolism, lipid metabolism, biogenic amine metabolism, amino acid metabolism, endothelial nitric oxide synthase signaling, and tRNA biosynthesis. Taken together, this data indicates broad metabolic dysregulation in Barth Syndrome with wide cellular effects.
[Mh] Termos MeSH primário: Síndrome de Barth/sangue
Síndrome de Barth/patologia
Cardiolipinas/sangue
Metabolômica
[Mh] Termos MeSH secundário: Adolescente
Adulto
Síndrome de Barth/genética
Cardiolipinas/genética
Criança
Pré-Escolar
Feminino
Seres Humanos
Lactente
Metabolismo dos Lipídeos/genética
Espectroscopia de Ressonância Magnética
Masculino
Redes e Vias Metabólicas/genética
Mitocôndrias/metabolismo
Mutação
Óxido Nítrico Sintase/sangue
Óxido Nítrico Sintase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Cardiolipins); EC 1.14.13.39 (Nitric Oxide Synthase)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170403
[Lr] Data última revisão:
170403
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160326
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0151802


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[PMID]:26908608
[Au] Autor:Lu YW; Galbraith L; Herndon JD; Lu YL; Pras-Raves M; Vervaart M; Van Kampen A; Luyf A; Koehler CM; McCaffery JM; Gottlieb E; Vaz FM; Claypool SM
[Ad] Endereço:Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2185, USA.
[Ti] Título:Defining functional classes of Barth syndrome mutation in humans.
[So] Source:Hum Mol Genet;25(9):1754-70, 2016 May 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The X-linked disease Barth syndrome (BTHS) is caused by mutations in TAZ; TAZ is the main determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, cardiolipin. To date, a detailed characterization of endogenous TAZ has only been performed in yeast. Further, why a given BTHS-associated missense mutation impairs TAZ function has only been determined in a yeast model of this human disease. Presently, the detailed characterization of yeast tafazzin harboring individual BTHS mutations at evolutionarily conserved residues has identified seven distinct loss-of-function mechanisms caused by patient-associated missense alleles. However, whether the biochemical consequences associated with individual mutations also occur in the context of human TAZ in a validated mammalian model has not been demonstrated. Here, utilizing newly established monoclonal antibodies capable of detecting endogenous TAZ, we demonstrate that mammalian TAZ, like its yeast counterpart, is localized to the mitochondrion where it adopts an extremely protease-resistant fold, associates non-integrally with intermembrane space-facing membranes and assembles in a range of complexes. Even though multiple isoforms are expressed at the mRNA level, only a single polypeptide that co-migrates with the human isoform lacking exon 5 is expressed in human skin fibroblasts, HEK293 cells, and murine heart and liver mitochondria. Finally, using a new genome-edited mammalian BTHS cell culture model, we demonstrate that the loss-of-function mechanisms for two BTHS alleles that represent two of the seven functional classes of BTHS mutation as originally defined in yeast, are the same when modeled in human TAZ.
[Mh] Termos MeSH primário: Síndrome de Barth/genética
Fibroblastos/metabolismo
Mitocôndrias Cardíacas/metabolismo
Mitocôndrias Hepáticas/metabolismo
Mutação/genética
Pele/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Animais
Síndrome de Barth/metabolismo
Síndrome de Barth/patologia
Células Cultivadas
Fibroblastos/citologia
Células HEK293
Seres Humanos
Camundongos
Mitocôndrias Cardíacas/patologia
Mitocôndrias Hepáticas/patologia
Isoformas de Proteínas
Pele/citologia
Fatores de Transcrição/classificação
Fatores de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Isoforms); 0 (TAZ protein, human); 0 (Transcription Factors)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160225
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddw046


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[PMID]:26853223
[Au] Autor:Ferri L; Dionisi-Vici C; Taurisano R; Vaz FM; Guerrini R; Morrone A
[Ad] Endereço:Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.
[Ti] Título:When silence is noise: infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription.
[So] Source:Clin Genet;90(5):461-465, 2016 Nov.
[Is] ISSN:1399-0004
[Cp] País de publicação:Denmark
[La] Idioma:eng
[Ab] Resumo:Barth syndrome (BTHS) is an X-linked inborn error of metabolism which affects males. The main manifestations are cardiomyopathy, myopathy, hypotonia, growth delay, intermittent neutropenia and 3-methylglutaconic aciduria. Diagnosis is confirmed by mutational analysis of the TAZ gene and biochemical dosage of the monolysocardiolipin/tetralinoleoyl cardiolipin (MLCL:L4-CL) ratio. We report a 6-year-old boy who presented with severe hypoglycemia, lactic acidosis and severe dilated cardiomyopathy soon after birth. The MLCL:L4-CL ratio confirmed BTHS (3.90 on patient's fibroblast, normal: 0-0.3). Subsequent sequencing of the TAZ gene revealed only the new synonymous variant NM_000116.3 (TAZ):c.348C>T p.(Gly116Gly), which did not appear to affect the protein sequence. In silico prediction analysis suggested the new c.348C>T nucleotide change could alter the TAZ mRNA splicing processing. We analyzed TAZ mRNAs in the patient's fibroblasts and found an abnormal skipping of 24 bases (NM_000116.3:c.346_371), with the consequent ablation of 8 amino acid residues in the tafazzin protein (NP_000107.1:p.Lys117_Gly124del). Molecular analysis of at risk female family members identified the patient's sister and mother as heterozygous carriers. Apparently harmless synonymous variants in the TAZ gene can damage gene expression. Such findings widen our knowledge of molecular heterogeneity in BTHS.
[Mh] Termos MeSH primário: Síndrome de Barth/genética
Cardiomiopatia Dilatada/genética
Fatores de Transcrição/genética
Transcrição Genética
[Mh] Termos MeSH secundário: Acidose Láctica/genética
Acidose Láctica/fisiopatologia
Síndrome de Barth/sangue
Síndrome de Barth/fisiopatologia
Cardiolipinas/sangue
Cardiomiopatia Dilatada/fisiopatologia
Criança
Éxons/genética
Feminino
Heterozigoto
Seres Humanos
Hipoglicemia/genética
Hipoglicemia/fisiopatologia
Lisofosfolipídeos/sangue
Masculino
Mutação
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cardiolipins); 0 (Lysophospholipids); 0 (TAZ protein, human); 0 (Transcription Factors); 0 (monolysocardiolipin); 0 (tetralinoleoylcardiolipin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170630
[Lr] Data última revisão:
170630
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160209
[St] Status:MEDLINE
[do] DOI:10.1111/cge.12756



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