A Novel Exonic Splicing Mutation in the TAZ (G4.5) Gene in a Case with Atypical Barth Syndrome

Fan, Yuxin; Steller, Jonathan; Gonzalez, Iris L.; Kulik, Wim; Fox, Michelle; Chang, Richard Y.; Westerfield, Brandy A; Batra, Anjan S.; Wang, Raymond Yu Jeang; Gallant, Natalie M.; Peña, Liana S.; Wang, Hu; Huang, Taosheng; Bhuta, Sunita; Penny, Daniel J.; McCabe, Edward R.B.; Kimonis, Virginia

doi:10.1007/8904_2013_228

Cited by 5 publications

(3 citation statements)

References 31 publications

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“…4 , Table 1 ). Functional RNA analysis proved that this mutation causes retention of intron 6 and partial deletion of exon 7, confirming pathogenicity (r.[541 + 1_542-1 ins; r.553_583del]; p.Lys182Glnfs*4) (Fan et al 2013 ). The mutation has not been modelled in yeast.…”

Section: Discussionmentioning

confidence: 78%

Barth syndrome without tetralinoleoyl cardiolipin deficiency: a possible ameliorated phenotype

Bowron

Honeychurch

Williams

et al. 2014

J of Inher Metab Disea

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Barth syndrome (BTHS) is an X-linked disorder characterised by cardiac and skeletal myopathy, growth delay, neutropenia and 3-methylglutaconic aciduria (3-MGCA). Patients have TAZ gene mutations which affect metabolism of cardiolipin, resulting in low tetralinoleoyl cardiolipin (CL4), an increase in its precursor, monolysocardiolipin (MLCL), and an increased MLCL/CL4 ratio. During development of a diagnostic service for BTHS, leukocyte CL4 was measured in 156 controls and 34 patients with genetically confirmed BTHS. A sub-group of seven subjects from three unrelated families was identified with leukocyte CL4 concentrations within the control range. This had led to initial false negative disease detection in two of these patients. MLCL/CL4 in this subgroup was lower than in other BTHS patients but higher than controls, with no overlap between the groups. TAZ gene mutations in these families are all predicted to be pathological. This report describes the clinical histories of these seven individuals with an atypical phenotype: some features were typical of BTHS (five have had cardiomyopathy, one family has a history of male infant deaths, three have growth delay and five have 3-MGCA) but none has persistent neutropenia, five have excellent exercise tolerance and two adults are asymptomatic. This report also emphasises the importance of measurement of MLCL/CL4 ratio rather than CL4 alone in the biochemical diagnosis of the BTHS.

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Section: Discussionmentioning

confidence: 78%

Barth syndrome without tetralinoleoyl cardiolipin deficiency: a possible ameliorated phenotype

Bowron

Honeychurch

Williams

et al. 2014

J of Inher Metab Disea

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“…Chen et al reported nine patients with familial EFE in four families inherited in X-linked recessive, autosomal dominant and autosomal recessive fashion [149]. Recent reports have associated mutations in the tafazzin (TAZ/G4.5) gene located on Xq28 with familial X-linked EFE and Barth syndrome, reported to result in structural changes in the foetal heart as early as 18 weeks of gestation [150,151]. In a summary, current evidence suggests that primary EFE is hereditary, occurs with no other demonstrable cause of unexplained HF while secondary EFE is associated with aortic stenosis or atresia and includes coarctation of the aorta, ventricular septal defect, anomalous origin of left coronary artery from the pulmonary artery, myocardial injury from any cause, and metabolic or carnitine deficiency.…”

Section: Aetiopathogenesismentioning

confidence: 99%

“…Endocardial thickening may be the consequence of persistent and increased wall tension in the ventricles possible secondary to injured myocardium, mitral regurgitation or both [140][141][142][143][144]. EFE is sporadic but familial cases have been reported [150,151]. The suggestions that EFE might have a viral aetiology stems from the observation of the similarity of its clinical presentation to that of chronic MC.…”

Section: Aetiopathogenesismentioning

confidence: 99%

Endomyocardial diseases cardiomyopathy: A review and pooled analysis of pathophysiology, diagnosis and clinical management

Albakri¹

2019

Trends in Res

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Endomyocardial diseases are a rare and poorly understood aetiology of cardiomyopathy (CM). Common endomyocardial diseases capable of causing CM are endomyocardial fibrosis (EMF), hypereosinophilic syndrome (HES) with cardiac involvement and endocardial fibroelastosis (EFE). The key pathogenic mechanisms of HES and EMF are sustained eosinophilia while EFE is cardiac anomalies, infections or genetics causing fibroelastic thickening of the endocardium and systolic dysfunction. However, the recent classifications by the American Heart Association and the European Society of Cardiology describe CM due to endomyocardial diseases within the restrictive CM phenotype yet they might be two clinically distinct entities. Endomyocardial diseases as a cause of CM also lack sufficient evidence to develop a clear understanding of their natural course, diagnosis and management. Available evidence rely largely on earlier studies that have not incorporated progressive changes in non-invasive cardiac imaging that have occurred over the decades. Improved understanding of the disease and diagnosis is essential since early diagnosis and treatment targeted at the cause is essential to improve efficacy and survival. This paper therefore reviews published data on CMs due to endomyocardial diseases with a focus on epidemiology, aetiology, pathological features, clinical presentation, diagnosis and management. Improved knowledge on aetiologies of CMs such as endomyocardial diseases is important to develop targeted treatment and improve both patient and clinical outcomes.

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Mis-sesnse mutations in Tafazzin (TAZ) that escort to mild clinical symptoms of Barth syndrome is owed to the minimal inhibitory effect of the mutations on the enzyme function: In-silico evidence

Debnath¹,

Addya²

2014

Interdiscip Sci Comput Life Sci

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Tafazzin (EC 2.3.1.23) is a Phospholipid Transacylase involved in Cardiolipin remodeling on mitochondrial membrane and coded by TAZ gene (Cytogenetic Location: Xq28) in human. Its mutations cause Barth syndrome (MIM ID: #302060)/3-Methyl Glutaconyl Aciduria Type II, an inborn error of metabolism often leading to foetal or infantile fatality. Nevertheless, some mis-sense mutations result in mild clinical symptoms. To evaluate the rationale of mild symptoms and for an insight of Tafazzin active site, sequence based and structure based ramifications of wild and mutant Tafazzins were compared in-silico. Sequence based domain predictions, surface accessibilities on substitution & conserved catalytic sites with statistical drifts, as well as thermal stability changes for the mutations and the interaction analysis of Tafazzin were performed. Crystal structure of Tafazzin is not yet resolved experimentally, therefore 3D coordinates of Tafazzin and its mutants were spawned through homology modeling. Energetically minimized and structurally validated models were used for comparative docking simulations. We analyzed active site geometry of the models in addition to calculating overall substrate binding efficiencies for each of the enzyme-ligand complex deduced from binding energies instead of comparing only the docking scores. Also, individual binding energies of catalytic residues on conserved HX4D motif of Acyltransferase superfamily present in Tafazzins were estimated. This work elucidates the basis of mild symptoms in patients with mis-sense mutations, identifies the most pathogenic mutant among others in the study and also divulges the critical role of HX4D domain towards successful transacylation by Taffazin. The in-silico observations are in complete agreement with clinical findings reported for the patients with mutations.

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A Novel Exonic Splicing Mutation in the TAZ (G4.5) Gene in a Case with Atypical Barth Syndrome

Abstract: The identification of a TAZ gene mutation, mRNA analysis, and monolysocardiolipin/cardiolipin ratio determination were important for the diagnosis and genetic counseling in this family with atypical Barth syndrome that was not found to be associated with 3-methylglutaconic aciduria.

Cited by 5 publications

References 31 publications

Barth syndrome without tetralinoleoyl cardiolipin deficiency: a possible ameliorated phenotype

Barth syndrome without tetralinoleoyl cardiolipin deficiency: a possible ameliorated phenotype

Endomyocardial diseases cardiomyopathy: A review and pooled analysis of pathophysiology, diagnosis and clinical management

Mis-sesnse mutations in Tafazzin (TAZ) that escort to mild clinical symptoms of Barth syndrome is owed to the minimal inhibitory effect of the mutations on the enzyme function: In-silico evidence

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