Research Report

JIMD Reports - Volume 11

Volume 11 of the series JIMD Reports pp 99-106

Date:

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

  • Yuxin FanAffiliated withJohn Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine
  • , Jon StellerAffiliated withChildren’s Hospital of Orange County and Department of Pediatrics, University of California Irvine
  • , Iris L. GonzalezAffiliated withNemours Biomedical Research Department, Alfred I. duPont Hospital for Children Email author 
  • , Wim KulikAffiliated withDepartment of Clinical Chemistry, University of Amsterdam, Laboratory Genetic Metabolic Diseases
  • , Michelle FoxAffiliated withDepartment of Pediatrics, University of California
  • , Richard ChangAffiliated withDivision of Metabolic Disorders, Children’s Hospital of Orange CountyChildren’s Hospital of Orange County and Department of Pediatrics, University of California Irvine
  • , Brandy A. WesterfieldAffiliated withJohn Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine
  • , Anjan S. BatraAffiliated withChildren’s Hospital of Orange County and Department of Pediatrics, University of California Irvine
  • , Raymond Yu Jeang WangAffiliated withDivision of Metabolic Disorders, Children’s Hospital of Orange CountyChildren’s Hospital of Orange County and Department of Pediatrics, University of California Irvine
    • , Natalie M. GallantAffiliated withDepartment of Pediatrics, University of California
    • , Liana S. PenaAffiliated withJohn Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine
    • , Hu WangAffiliated withJohn Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine
    • , Taosheng HuangAffiliated withChildren’s Hospital of Orange County and Department of Pediatrics, University of California Irvine
    • , Sunita BhutaAffiliated withDepartment of Pathology, University of California
    • , Daniel J. PennyAffiliated withJohn Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine
    • , Edward R. McCabeAffiliated withDepartment of Pediatrics, University of CaliforniaLinda Crnic Institute for Down Syndrome, University of Colorado School of Medicine
    • , Virginia E. KimonisAffiliated withChildren’s Hospital of Orange County and Department of Pediatrics, University of California IrvineUCI Division of Genetics and Metabolism, Dept. of Pediatrics, Univ. of California-Irvine Med. Center Email author 

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Abstract

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.

Patient & Methods: The 4-month-old proband presented with respiratory distress, neutropenia, and dilated cardiomyopathy with reduced ejection fraction of 10%. No 3-methylglutaconic aciduria was detected on repeated urine organic acid analyses. Family history indicated that his maternal uncle died of endocardial fibroelastosis and dilated cardiomyopathy at 26 months. TAZ DNA sequencing, mRNA analysis, and cardiolipin analysis were performed.

Results: A novel nucleotide substitution c.553A>G in exon 7 of the TAZ gene was identified in the proband, predicting an amino acid substitution p.Met185Val. However, this mutation created a new splice donor signal within exon 7 causing mis-splicing of the message, producing two messages that only differ in the presence/absence of exon 5; these retain intron 6 and have only 11 bases of exon 7. Cardiolipin analysis confirmed the loss of tafazzin activity. The proband’s mother, maternal aunt, and grandmother carry the same mutation.

Conclusions: 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.