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Michael Schlame - One of the best experts on this subject based on the ideXlab platform.
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aav gene therapy prevents and reverses heart failure in a murine knockout model of barth syndrome
Circulation Research, 2020Co-Authors: Suya Wang, Yang Xu, Michael Schlame, Douglas Strathdee, Yifei Li, Vassilios J Bezzerides, William T PuAbstract:Rationale: Barth syndrome is an X-linked cardiac and skeletal myopathy caused by mutation of the gene Tafazzin (TAZ). Currently, there is no targeted treatment for Barth syndrome. Lack of a proper ...
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the function of Tafazzin a mitochondrial phospholipid lysophospholipid acyltransferase
Journal of Molecular Biology, 2020Co-Authors: Michael Schlame, Yang XuAbstract:Abstract Tafazzin is a mitochondrial enzyme that exchanges fatty acids between phospholipids by phospholipid-lysophospholipid transacylation. The reaction alters the molecular species composition and, as a result, the physical properties of lipids. In vivo, the most important substrate of Tafazzin is the mitochondria-specific lipid cardiolipin. Tafazzin mutations cause the human disease Barth syndrome, which presents with cardiomyopathy, skeletal muscle weakness, fatigue, and other symptoms, probably all related to mitochondrial dysfunction. The reason why mitochondria require Tafazzin is still not known but recent evidence suggests that Tafazzin may lower the energy cost associated with protein crowding in the inner mitochondrial membrane.
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plasmalogen loss caused by remodeling deficiency in mitochondria
Life Science Alliance, 2019Co-Authors: Tomohiro Kimura, Yang Xu, Michael Schlame, Bob Berno, Atsuko K Kimura, Vernon Monteiro, Richard M EpandAbstract:Lipid homeostasis is crucial in human health. Barth syndrome (BTHS), a life-threatening disease typically diagnosed with cardiomyopathy and neutropenia, is caused by mutations in the mitochondrial transacylase Tafazzin. By high-resolution 31P nuclear magnetic resonance (NMR) with cryoprobe technology, recently we found a dramatic loss of choline plasmalogen in the Tafazzin-knockdown (TAZ-KD) mouse heart, besides observing characteristic cardiolipin (CL) alterations in BTHS. In inner mitochondrial membrane where Tafazzin locates, CL and diacyl phosphatidylethanolamine are known to be essential via lipid–protein interactions reflecting their cone shape for integrity of respiratory chain supercomplexes and cristae ultrastructure. Here, we investigate the TAZ-KD brain, liver, kidney, and lymphoblast from patients compared with controls. We identified common yet markedly cell type–dependent losses of ethanolamine plasmalogen as the dominant plasmalogen class therein. Tafazzin function thus critically relates to homeostasis of plasmalogen, which in the ethanolamine class has conceivably analogous and more potent molecular functions in mitochondria than diacyl phosphatidylethanolamine. The present discussion of a loss of plasmalogen–protein interaction applies to other diseases with mitochondrial plasmalogen loss and aberrant forms of this organelle, including Alzheimer9s disease.
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Assembly of the complexes of oxidative phosphorylation triggers the remodeling of cardiolipin.
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Yang Xu, Miriam L Greenberg, Murari Anjaneyulu, Alec Donelian, Wenxi Yu, Edward Owusu-ansah, Michael SchlameAbstract:Cardiolipin (CL) is a mitochondrial phospholipid with a very specific and functionally important fatty acid composition, generated by Tafazzin. However, in vitro Tafazzin catalyzes a promiscuous acyl exchange that acquires specificity only in response to perturbations of the physical state of lipids. To identify the process that imposes acyl specificity onto CL remodeling in vivo, we analyzed a series of deletions and knockdowns in Saccharomyces cerevisiae and Drosophila melanogaster, including carriers, membrane homeostasis proteins, fission-fusion proteins, cristae-shape controlling and MICOS proteins, and the complexes I–V. Among those, only the complexes of oxidative phosphorylation (OXPHOS) affected the CL composition. Rather than any specific complex, it was the global impairment of the OXPHOS system that altered CL and at the same time shortened its half-life. The knockdown of OXPHOS expression had the same effect on CL as the knockdown of Tafazzin in Drosophila flight muscles, including a change in CL composition and the accumulation of monolyso-CL. Thus, the assembly of OXPHOS complexes induces CL remodeling, which, in turn, leads to CL stabilization. We hypothesize that protein crowding in the OXPHOS system imposes packing stress on the lipid bilayer, which is relieved by CL remodeling to form tightly packed lipid–protein complexes.
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loss of Tafazzin results in decreased myoblast differentiation in c2c12 cells a myoblast model of barth syndrome and cardiolipin deficiency
Biochimica et Biophysica Acta, 2018Co-Authors: Christian A Reynolds, Michael Schlame, Yiran Li, Maik Huttemann, David A Stevenson, Douglas Strathdee, Miriam L GreenbergAbstract:Abstract Barth syndrome (BTHS) is an X-linked genetic disorder resulting from mutations in the Tafazzin gene (TAZ), which encodes the transacylase that remodels the mitochondrial phospholipid cardiolipin (CL). While most BTHS patients exhibit pronounced skeletal myopathy, the mechanisms linking defective CL remodeling and skeletal myopathy have not been determined. In this study, we constructed a CRISPR-generated stable Tafazzin knockout (TAZ-KO) C2C12 myoblast cell line. TAZ-KO cells exhibit mitochondrial deficits consistent with other models of BTHS, including accumulation of monolyso-CL (MLCL), decreased mitochondrial respiration, and increased mitochondrial ROS production. Additionally, Tafazzin deficiency was associated with impairment of myocyte differentiation. Future studies should determine whether alterations in myogenic determination contribute to the skeletal myopathy observed in BTHS patients. The BTHS myoblast model will enable studies to elucidate mechanisms by which defective CL remodeling interferes with normal myocyte differentiation and skeletal muscle ontogenesis.
Yang Xu - One of the best experts on this subject based on the ideXlab platform.
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aav gene therapy prevents and reverses heart failure in a murine knockout model of barth syndrome
Circulation Research, 2020Co-Authors: Suya Wang, Yang Xu, Michael Schlame, Douglas Strathdee, Yifei Li, Vassilios J Bezzerides, William T PuAbstract:Rationale: Barth syndrome is an X-linked cardiac and skeletal myopathy caused by mutation of the gene Tafazzin (TAZ). Currently, there is no targeted treatment for Barth syndrome. Lack of a proper ...
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the function of Tafazzin a mitochondrial phospholipid lysophospholipid acyltransferase
Journal of Molecular Biology, 2020Co-Authors: Michael Schlame, Yang XuAbstract:Abstract Tafazzin is a mitochondrial enzyme that exchanges fatty acids between phospholipids by phospholipid-lysophospholipid transacylation. The reaction alters the molecular species composition and, as a result, the physical properties of lipids. In vivo, the most important substrate of Tafazzin is the mitochondria-specific lipid cardiolipin. Tafazzin mutations cause the human disease Barth syndrome, which presents with cardiomyopathy, skeletal muscle weakness, fatigue, and other symptoms, probably all related to mitochondrial dysfunction. The reason why mitochondria require Tafazzin is still not known but recent evidence suggests that Tafazzin may lower the energy cost associated with protein crowding in the inner mitochondrial membrane.
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plasmalogen loss caused by remodeling deficiency in mitochondria
Life Science Alliance, 2019Co-Authors: Tomohiro Kimura, Yang Xu, Michael Schlame, Bob Berno, Atsuko K Kimura, Vernon Monteiro, Richard M EpandAbstract:Lipid homeostasis is crucial in human health. Barth syndrome (BTHS), a life-threatening disease typically diagnosed with cardiomyopathy and neutropenia, is caused by mutations in the mitochondrial transacylase Tafazzin. By high-resolution 31P nuclear magnetic resonance (NMR) with cryoprobe technology, recently we found a dramatic loss of choline plasmalogen in the Tafazzin-knockdown (TAZ-KD) mouse heart, besides observing characteristic cardiolipin (CL) alterations in BTHS. In inner mitochondrial membrane where Tafazzin locates, CL and diacyl phosphatidylethanolamine are known to be essential via lipid–protein interactions reflecting their cone shape for integrity of respiratory chain supercomplexes and cristae ultrastructure. Here, we investigate the TAZ-KD brain, liver, kidney, and lymphoblast from patients compared with controls. We identified common yet markedly cell type–dependent losses of ethanolamine plasmalogen as the dominant plasmalogen class therein. Tafazzin function thus critically relates to homeostasis of plasmalogen, which in the ethanolamine class has conceivably analogous and more potent molecular functions in mitochondria than diacyl phosphatidylethanolamine. The present discussion of a loss of plasmalogen–protein interaction applies to other diseases with mitochondrial plasmalogen loss and aberrant forms of this organelle, including Alzheimer9s disease.
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Assembly of the complexes of oxidative phosphorylation triggers the remodeling of cardiolipin.
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Yang Xu, Miriam L Greenberg, Murari Anjaneyulu, Alec Donelian, Wenxi Yu, Edward Owusu-ansah, Michael SchlameAbstract:Cardiolipin (CL) is a mitochondrial phospholipid with a very specific and functionally important fatty acid composition, generated by Tafazzin. However, in vitro Tafazzin catalyzes a promiscuous acyl exchange that acquires specificity only in response to perturbations of the physical state of lipids. To identify the process that imposes acyl specificity onto CL remodeling in vivo, we analyzed a series of deletions and knockdowns in Saccharomyces cerevisiae and Drosophila melanogaster, including carriers, membrane homeostasis proteins, fission-fusion proteins, cristae-shape controlling and MICOS proteins, and the complexes I–V. Among those, only the complexes of oxidative phosphorylation (OXPHOS) affected the CL composition. Rather than any specific complex, it was the global impairment of the OXPHOS system that altered CL and at the same time shortened its half-life. The knockdown of OXPHOS expression had the same effect on CL as the knockdown of Tafazzin in Drosophila flight muscles, including a change in CL composition and the accumulation of monolyso-CL. Thus, the assembly of OXPHOS complexes induces CL remodeling, which, in turn, leads to CL stabilization. We hypothesize that protein crowding in the OXPHOS system imposes packing stress on the lipid bilayer, which is relieved by CL remodeling to form tightly packed lipid–protein complexes.
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substantial decrease in plasmalogen in the heart associated with Tafazzin deficiency
Biochemistry, 2018Co-Authors: Tomohiro Kimura, Yang Xu, Michael Schlame, Bob Berno, Atsuko K Kimura, Richard M EpandAbstract:Tafazzin is the mitochondrial enzyme that catalyzes transacylation between a phospholipid and a lysophospholipid in remodeling. Mutations in Tafazzin cause Barth syndrome, a potentially life-threatening disease with the major symptom being cardiomyopathy. In the Tafazzin-deficient heart, cardiolipin (CL) acyl chains become abnormally heterogeneous unlike those in the normal heart with a single dominant linoleoyl species, tetralinoleoyl CL. In addition, the amount of CL decreases and monolysocardiolipin (MLCL) accumulates. Here we determine using high-resolution 31P nuclear magnetic resonance with cryoprobe technology the fundamental phospholipid composition, including the major but oxidation-labile plasmalogens, in the Tafazzin-knockdown (TAZ-KD) mouse heart as a model of Barth syndrome. In addition to confirming a lower level of CL (6.4 ± 0.1 → 2.0 ± 0.4 mol % of the total phospholipid) and accumulation of MLCL (not detected → 3.3 ± 0.5 mol %) in the TAZ-KD, we found a substantial reduction in the level ...
Ashim Malhotra - One of the best experts on this subject based on the ideXlab platform.
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the phospholipid transacylase Tafazzin is a drug target for overcoming chemoresistance in pancreatic cancer
The FASEB Journal, 2016Co-Authors: Adeleke Badejo, Jordan Mccreary, Ashim MalhotraAbstract:Pancreatic cancer has a high mortality, and low 5-year prognosis. Discovery of novel therapeutic targets is an urgent need. Tafazzin remodels the inner mitochondrial membrane phospholipid cardiolip...
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Tafazzins from Drosophila and mammalian cells assemble in large protein complexes with a short half-life.
Mitochondrion, 2015Co-Authors: Yang Xu, Steven M Claypool, Ashim Malhotra, Michael SchlameAbstract:Abstract Tafazzin is a transacylase that affects cardiolipin fatty acid composition and mitochondrial function. Mutations in human Tafazzin cause Barth syndrome yet the enzyme has mostly been characterized in yeast. To study Tafazzin in higher organisms, we isolated mitochondria from Drosophila and mammalian cell cultures. Our data indicate that Tafazzin binds to multiple protein complexes in these organisms, and that the interactions of Tafazzin lack strong specificity. Very large Tafazzin complexes could only be detected in the presence of cardiolipin, but smaller complexes remained intact even upon treatment with phospholipase A2. In mammalian cells, Tafazzin had a half-life of only 3–6 h, which was much shorter than the half-life of other mitochondrial proteins. The data suggest that Tafazzin is a transient resident of multiple protein complexes.
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Pharmacogenomic considerations in the treatment of the pediatric cardiomyopathy called Barth syndrome.
Recent Patents on Biotechnology, 2014Co-Authors: Ashim Malhotra, Parmbir Kahlon, Timothy Donoho, Ian C. DoyleAbstract:Barth syndrome (BTHS) is a genetic, X-linked, rare but often fatal, pediatric skeletal- and cardiomyopathy occurring due to mutations in the Tafazzin gene (TAZ). TAZ encodes a transacylase involved in phospholipid biosynthesis, also called Tafazzin, which is responsible for remodeling the inner mitochondrial membrane phospholipid, cardiolipin (CL). Tafazzin mutations lead to compositional alterations in CL molecular species, causing extensive mitochondrial aberrations and ultrastructural muscle damage. There are no specific treatments or cure for BTHS. Current therapy is largely palliative and aimed at treatment of organ-specific complications during disease progression. Polypharmacy frequently occurs during treatment and may lead to severe adverse events. Adverse reactions may originate from exogenous factors such as the inadvertent co-administration of contraindicated drugs. Theoretically, endogenous factors such as polymorphic variations in genes encoding drug metabolizing enzymes may also precipitate fatal toxicity. Investigation of the consequences of pharmacogenomic variations on BTHS therapy is lacking. To our knowledge, this review presents the first examination of the possible sources of pharmacogenomic variations that may affect BTHS therapy. We also explore BTHSspecific patents for possible treatment options. The patents discussed suggest innovative strategies for treatment, including feeding linoleic acid to patients to overcome compositional CL deficiency; or the use of 2S,4R ketoconazole formulations to augment CL levels; or the delivery of mitochondrial stabilizing cargo. Future research directions are also discussed.
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characterization of Tafazzin splice variants from humans and fruit flies
Journal of Biological Chemistry, 2009Co-Authors: Yang Xu, Ashim Malhotra, Shali Zhang, Irit Edelmannovemsky, Antonina Kruppa, Carolina Cernicica, Steven Blais, Thomas A Neubert, Michael SchlameAbstract:The Tafazzin gene encodes a phospholipid-lysophospholipid transacylase involved in cardiolipin metabolism, but it is not known why it forms multiple transcripts as a result of alternative splicing. Here we studied the intracellular localization, enzymatic activity, and metabolic function of four isoforms of human Tafazzin and three isoforms of Drosophila Tafazzin upon expression in different mammalian and insect systems. When expressed in HeLa cells, all isoforms were localized in mitochondria except for the B-form of Drosophila Tafazzin, which was associated with multiple intracellular membranes. Among the human isoforms, only full-length Tafazzin (FL) and Tafazzin lacking exon 5 (Δ5) had transacylase activity, and only these two isoforms were able to restore a normal cardiolipin pattern, normal respiratory activity of mitochondria, and male fertility in Tafazzin-deficient flies. Both FL and Δ5 were associated with large protein complexes in 293T cell mitochondria, but treatment with alkali and proteinase K suggested that the Δ5 isoform was more integrated into the hydrophobic core of the membrane than the FL isoform. Although all Drosophila isoforms showed transacylase activity in vitro, only the A-form supported cardiolipin remodeling in flies. The data suggest that humans express two mitochondrial isoenzymes of Tafazzin that have similar transacylase activities but different membrane topologies. Furthermore, the data show that the expression of human Tafazzin in flies creates cardiolipin with a Drosophila pattern, suggesting that the characteristic fatty acid profile of cardiolipin is not determined by the substrate specificity of Tafazzin.
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distinct effects of Tafazzin deletion in differentiated and undifferentiated mitochondria
Mitochondrion, 2009Co-Authors: Devrim Acehan, Ashim Malhotra, Riekelt H Houtkooper, Zaza Khuchua, David L Stokes, Johanna Kaufman, Howard A Rockman, Michael SchlameAbstract:Abstract Tafazzin is a conserved mitochondrial protein that is required to maintain normal content and composition of cardiolipin. We used electron tomography to investigate the effect of Tafazzin deletion on mitochondrial structure and found that cellular differentiation plays a crucial role in the manifestation of abnormalities. This conclusion was reached by comparing differentiated cardiomyocytes with embryonic stem cells from mouse and by comparing different tissues from Drosophila melanogaster. The data suggest that Tafazzin deficiency affects cardiolipin in all mitochondria, but significant alterations of the ultrastructure, such as remodeling and aggregation of inner membranes, will only occur after specific differentiation.
Riekelt H Houtkooper - One of the best experts on this subject based on the ideXlab platform.
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deletion of the cardiolipin specific phospholipase cld1 rescues growth and lifespan defects in the Tafazzin mutant implications for barth syndrome 605 4
The FASEB Journal, 2014Co-Authors: Cunqi Ye, Riekelt H Houtkooper, Yiran Li, Iliana A Chatzispyrou, Maik Huttemann, Shuliang Chen, Miriam L GreenbergAbstract:Cardiolipin (CL) that is synthesized de novo is deacylated to monolysocardiolipin (MLCL), which is reacylated by Tafazzin. Remodeled CL contains mostly unsaturated fatty acids. In eukaryotes, loss of Tafazzin leads to growth and respiration defects and, in humans, results in the life-threatening disorder Barth syndrome (BTHS). Tafazzin deficiency causes a decrease in the CL/MLCL ratio and decreased unsaturated CL species. Which of these biochemical outcomes contributes to the physiological defects is not known. Yeast cells have a single CL-specific phospholipase, Cld1, which can be exploited to distinguish between these outcomes. The cld1Δ mutant has decreased unsaturated CL, but the CL/MLCL ratio is similar to that of wild type cells. We show that cld1Δ rescues growth, life span, and respiratory defects of the taz1Δ mutant. This suggests that defective growth and respiration in Tafazzin-deficient cells is caused by the decreased CL/MLCL ratio, not by a deficiency in unsaturated CL. CLD1 expression is inc...
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deletion of the cardiolipin specific phospholipase cld1 rescues growth and life span defects in the Tafazzin mutant implications for barth syndrome
Journal of Biological Chemistry, 2014Co-Authors: Cunqi Ye, Riekelt H Houtkooper, Yiran Li, Iliana A Chatzispyrou, Maik Huttemann, Shuliang Chen, Miriam L GreenbergAbstract:Cardiolipin (CL) that is synthesized de novo is deacylated to monolysocardiolipin (MLCL), which is reacylated by Tafazzin. Remodeled CL contains mostly unsaturated fatty acids. In eukaryotes, loss of Tafazzin leads to growth and respiration defects, and in humans, this results in the life-threatening disorder Barth syndrome. Tafazzin deficiency causes a decrease in the CL/MLCL ratio and decreased unsaturated CL species. Which of these biochemical outcomes contributes to the physiological defects is not known. Yeast cells have a single CL-specific phospholipase, Cld1, that can be exploited to distinguish between these outcomes. The cld1Δ mutant has decreased unsaturated CL, but the CL/MLCL ratio is similar to that of wild type cells. We show that cld1Δ rescues growth, life span, and respiratory defects of the taz1Δ mutant. This suggests that defective growth and respiration in Tafazzin-deficient cells are caused by the decreased CL/MLCL ratio and not by a deficiency in unsaturated CL. CLD1 expression is increased during respiratory growth and regulated by the heme activator protein transcriptional activation complex. Overexpression of CLD1 leads to decreased mitochondrial respiration and growth and instability of mitochondrial DNA. However, ATP concentrations are maintained by increasing glycolysis. We conclude that transcriptional regulation of Cld1-mediated deacylation of CL influences energy metabolism by modulating the relative contribution of glycolysis and respiration.
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Cardiac and Skeletal Muscle Defects in a Mouse Model of Human Barth Syndrome
Journal of Biological Chemistry, 2010Co-Authors: Devrim Acehan, Riekelt H Houtkooper, Willem Kulik, Jeanne James, Vicky Moore, Chonan Tokunaga, Janaka Wansapura, Matthew J. Toth, Arnold W StraussAbstract:Barth syndrome is an X-linked genetic disorder caused by mutations in the Tafazzin (taz) gene and characterized by dilated cardiomyopathy, exercise intolerance, chronic fatigue, delayed growth, and neutropenia. Tafazzin is a mitochondrial transacylase required for cardiolipin remodeling. Although Tafazzin function has been studied in non-mammalian model organisms, mammalian genetic loss of function approaches have not been used. We examined the consequences of Tafazzin knockdown on sarcomeric mitochondria and cardiac function in mice. Tafazzin knockdown resulted in a dramatic decrease of tetralinoleoyl cardiolipin in cardiac and skeletal muscles and accumulation of monolysocardiolipins and cardiolipin molecular species with aberrant acyl groups. Electron microscopy revealed pathological changes in mitochondria, myofibrils, and mitochondrion-associated membranes in skeletal and cardiac muscles. Echocardiography and magnetic resonance imaging revealed severe cardiac abnormalities, including left ventricular dilation, left ventricular mass reduction, and depression of fractional shortening and ejection fraction in Tafazzin-deficient mice. Tafazzin knockdown mice provide the first mammalian model system for Barth syndrome in which the pathophysiological relationships between altered content of mitochondrial phospholipids, ultrastructural abnormalities, myocardial and mitochondrial dysfunction, and clinical outcome can be completely investigated.
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the enigmatic role of Tafazzin in cardiolipin metabolism
Biochimica et Biophysica Acta, 2009Co-Authors: Riekelt H Houtkooper, Marjolein Turkenburg, Bwee Tien Pollthe, Daniela Karall, Celia Perezcerda, Amelia Morrone, Sabrina Malvagia, Ronald J A Wanders, Willem KulikAbstract:The mitochondrial phospholipid cardiolipin plays an important role in cellular metabolism as exemplified by its involvement in mitochondrial energy production and apoptosis. Following its biosynthesis, cardiolipin is actively remodeled to achieve its final acyl composition. An important cardiolipin remodeling enzyme is Tafazzin, of which several mRNA splice variants exist. Mutations in the Tafazzin gene cause the X-linked recessive disorder Barth syndrome. In addition to providing an overview of the current knowledge in literature about Tafazzin, we present novel experimental data and use this to discuss the functional role of the different Tafazzin variants in cardiolipin metabolism in relation to Barth syndrome. We developed and performed specific quantitative PCR analyses of different Tafazzin mRNA splice variants in 16 human tissues and correlated this with the tissue cardiolipin profile. In BTHS fibroblasts we showed that mutations in the Tafazzin gene affected both the level and distribution of Tafazzin mRNA variants. Transient expression of selected human Tafazzin variants in BTHS fibroblasts showed for the first time in a human cell system that Tafazzin lacking exon5 indeed functions in cardiolipin remodeling. (C) 2009 Elsevier B.V. All rights reserved.
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distinct effects of Tafazzin deletion in differentiated and undifferentiated mitochondria
Mitochondrion, 2009Co-Authors: Devrim Acehan, Ashim Malhotra, Riekelt H Houtkooper, Zaza Khuchua, David L Stokes, Johanna Kaufman, Howard A Rockman, Michael SchlameAbstract:Abstract Tafazzin is a conserved mitochondrial protein that is required to maintain normal content and composition of cardiolipin. We used electron tomography to investigate the effect of Tafazzin deletion on mitochondrial structure and found that cellular differentiation plays a crucial role in the manifestation of abnormalities. This conclusion was reached by comparing differentiated cardiomyocytes with embryonic stem cells from mouse and by comparing different tissues from Drosophila melanogaster. The data suggest that Tafazzin deficiency affects cardiolipin in all mitochondria, but significant alterations of the ultrastructure, such as remodeling and aggregation of inner membranes, will only occur after specific differentiation.
Iris L. Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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Tafazzin splice variants and mutations in barth syndrome
Molecular Genetics and Metabolism, 2014Co-Authors: Susan M Kirwin, Athena Manolakos, Sarah Swain Barnett, Iris L. GonzalezAbstract:article i nfo Article history: Barth syndrome is caused by mutations in the TAZ (Tafazzin) gene on human chromosome Xq28. The human Tafazzin gene produces four major mRNA splice variants; two of which have been shown to be functional (TAZ lacking exon 5 and full-length) in complementation studies with yeast and Drosophila. This study characterizes the multiple alternative splice variants of TAZ mRNA and their proportions in blood samples from a cohort of individuals with Barth syndrome (BTHS). Because it has been reported that collection and processing methods can affect the expression of various genes, we tested and chose a stabilizing medium for collecting, shipping and processing of the blood samples of these individuals. In both healthy controls and in BTHS individuals, we found a greater variety of alternatively spliced forms than previously described, with a sizeable proportion of minor splice variants besides the four dominant isoforms. Individuals with certain exonic and intronic splice mutations produce additional mutant mRNAs that could be translated into two or more proteins with different amino acid substitutions in a single individual. A fraction of the minor splice variants is predicted to be non- productive.
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A Novel Exonic Splicing Mutation in the TAZ (G4.5) Gene in a Case with Atypical Barth Syndrome.
JIMD reports, 2013Co-Authors: Jon Steller, Iris L. Gonzalez, Wim Kulik, Richard Chang, Brandy A. Westerfield, Anjan S. Batra, Raymond Y. Wang, Natalie M. GallantAbstract:Objective: Barth syndrome is an X-linked recessive disorder characterized by dilated cardiomyopathy, neutropenia, 3-methylglutaconic aciduria, abnormal mitochondria, variably expressed skeletal myopathy, and growth delay. The disorder is caused by mutations in the Tafazzin (TAZ/G4.5) gene located on Xq28. We report a novel exonic splicing mutation in the TAZ gene in a patient with atypical Barth syndrome.
