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.
D'Adamo P, Fassone L, Gedeon A et al (1997) The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies. Am J Hum Genet 61(4):862–867PubMedCrossRefGoogle Scholar
Dogan RI, Getoor L, Wilbur WJ et al (2007) SplicePort–an interactive splice-site analysis tool. Nucleic Acids Res 35(Web Server issue):W285–W291, Epub 2007 Jun 18PubMedCrossRefGoogle Scholar
Gedeon AK, Wilson MJ, Colley AC et al (1995) X linked fatal infantile cardiomyopathy maps to Xq28 and is possibly allelic to Barth syndrome. J Med Genet 32:383–388PubMedCrossRefGoogle Scholar
Gonzalez IL (2005) Barth syndrome: TAZ gene mutations, mRNAs, and evolution. Am J Med Genet A 134(4):409–414PubMedGoogle Scholar
Houtkooper RH, Rodenburg RJ, Thiels C et al (2009) Cardiolipin and monolysocardiolipin analysis in fibroblasts, lymphocytes, and tissues using high-performance liquid chromatography-mass spectrometry as a diagnostic test for Barth syndrome. Anal Biochem 387(2):230–237PubMedCrossRefGoogle Scholar
Johnston J, Kelley RI, Feigenbaum A et al (1997) Mutation characterization and genotype-phenotype correlation in Barth syndrome. Am J Hum Genet 61(5):1053–1058PubMedCrossRefGoogle Scholar
Kelley RI, Cheatham JP, Clark BJ et al (1991) X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria. J Pediatr 119(5):738–747PubMedCrossRefGoogle Scholar
Kulik W, van Lenthe H, Stet FS et al (2008) Bloodspot assay using HPLC-tandem mass spectrometry for detection of Barth syndrome. Clin Chem 54(2):371–378PubMedCrossRefGoogle Scholar
Malhotra A, Edelman-Novemsky I, Xu Y et al (2009) Role of calcium-independent phospholipase A2 in the pathogenesis of Barth Syndrome. Proc Natl Acad Sci U S A 106(7):2337–2341PubMedCrossRefGoogle Scholar
Marziliano N, Mannarino S, Nespoli L et al (2007) Barth syndrome associated with compound hemizygosity and heterozygosity of the TAZ and LDB3 genes. Am J Med Genet A 143A(9):907–915PubMedCrossRefGoogle Scholar
Roberts AE, Nixon C, Steward CG et al (2012) The Barth Syndrome Registry: distinguishing disease characteristics and growth data from a longitudinal study. Am J Med Genet Part A 158A:2726–2732PubMedCrossRefGoogle Scholar
Sakamoto O, Ohura T, Katsushima Y et al (2001) A novel intronic mutation of the TAZ ( G4.5) gene in a patient with Barth syndrome: creation of a 5' splice donor site with variant GC consensus and elongation of the upstream exon. Hum Genet 109(5):559–563PubMedCrossRefGoogle Scholar
Sakamoto O, Kitoh T, Ohura T et al (2002) Novel missense mutation (R94S) in the TAZ (G4.5) gene in a Japanese patient with Barth syndrome. J Hum Genet 47(5):229–231PubMedCrossRefGoogle Scholar
Schlame M, Rua D, Greenberg ML (2000) The biosynthesis and functional role of cardiolipin. Prog Lipid Res 39(3):257–288PubMedCrossRefGoogle Scholar
Schlame M, Towbin JA, Heerdt PM et al (2002) Deficiency of tetralinoleoyl-cardiolipin in Barth syndrome. Ann Neurol 51(5):634–637PubMedCrossRefGoogle Scholar
Schmidt MR, Birkebaek N, Gonzalez I et al (2004) Barth syndrome without 3-methylglutaconic aciduria. Acta Paediatr 93(3):419–421PubMedCrossRefGoogle Scholar
Spencer CT, Bryant RM, Day J et al (2006) Cardiac and clinical phenotype in Barth syndrome. Pediatrics 118(2):e337–e346PubMedCrossRefGoogle Scholar
Steward CG, Newbury-Ecob RA, Hastings R et al (2010) Barth Syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth. Prenal Diagn 30(10):970–976CrossRefGoogle Scholar
Valianpour F, Wanders RJ, Overmars H et al (2002) Cardiolipin deficiency in X-linked cardioskeletal myopathy and neutropenia (Barth syndrome, MIM 302060): a study in cultured skin fibroblasts. J Pediatr 141(5):729–733PubMedCrossRefGoogle Scholar
Vreken P, Valianpour F, Nijtmans LG et al (2000) Defective remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome. Biochem Biophys Res Commun 279(2):378–382PubMedCrossRefGoogle Scholar
Xu Y, Condell M, Plesken H et al (2006) A Drosophila model of Barth syndrome. Proc Natl Acad Sci U S A 103(31):11584–11588PubMedCrossRefGoogle Scholar