Molecular Genetics of Barth Syndrome


Barth syndrome (OMIM #302060) (BTHS) is an X‐linked disorder of lipid metabolism characterised by cardiomyopathy, skeletal myopathy, neutropaenia, growth delays and 3‐methylglutaconic aciduria. The causative mutations for BTHS are in the TAZ gene, which encode a putative acyltransferase named tafazzin, involved in the remodelling of cardiolipin (CL) in the inner mitochondrial membranes. To date, more than 120 different disease‐causing TAZ gene mutations have been reported. Mutations in the TAZ gene cause accumulation of monolysoCL and reduced levels of tetralinoeoyl CL, which result in mitochondrial structural and functional abnormalities. The functional role of CL has been investigated using model systems for BTHS such as yeast, zebrafish and flies. Recently, an inducible tafazzin knockdown mouse demonstrated abnormal fetal heart development with altered mitochondrial ultrastructure. Current understanding of the molecular genetics of BTHS including CL metabolism, mitochondrial disorders and clinical presentations are reviewed.

Key Concepts:

  • Barth syndrome is an X‐linked disorder of lipid metabolism characterised by cardiomyopathy, skeletal myopathy, neutropaenia, growth delays and 3‐methylglutaconic aciduria.

  • Barth syndrome is recognised as cardiolipin remodelling disorder due to the TAZ mutation.

  • TAZ gene encodes tafazzin protein, which has a central role in the reacylation of MLCL to L4‐CL in the mitochondria.

  • Cardiolipin plays a crucial role for both mitochondrial membrane structure and function.

  • The role of tafazzin and cardiolipin in the mitochondria remains to be elucidated.

  • Several model systems for Barth syndrome have been developed to elucidate the disease pathophysiology.

  • Mouse model of Barth syndrome provide new insight into the role of tafazzin.

Keywords: Barth syndrome (BTHS); TAZ gene; tafazzin; cardiolipin remodelling; tetralinoeoyl cardiolipin (L4‐CL); mitochondria

Figure 1.

INVM in a patient with BTHS. Left ventricular short axis view during echocardiography (a) and fast steady‐state cine magnetic resonance (MR) imaging (b) shows INVM. Noncompacted layer (NC) and compacted layer (C) are indicated in yellow and red bar, respectively. Diagnostic criteria is maximal end‐systolic NC/C>2 by echocardiography, or end‐diastolic NC/C>2.3 by MR imaging. Reproduced with permission from Takeda et al.. © Springer.

Figure 2.

Schematic representation of the TAZ gene. Two ATG initiation sites are indicated as ATG1 and ATG2. Exonic and intronic disease‐causing mutations are indicated above and below the TAZ gene, respectively. Data from the Human Tafazzin (TAZ) Gene Mutation and Variation Database.

Figure 3.

Multialignment of the amino acid sequence of tafazzin. Amino acid identities are indicated by grey squares. BTHS mutations are indicated above the amino acid and disease‐mutated residues are labelled in red. Data from the Human Tafazzin (TAZ) Gene Mutation and Variation Database. The black bar and the blue bar below the amino acid sequence indicate conserved acyltransferase motifs (A‐E) and integral interfacial membrane anchor, respectively. The red bar and the black bar below the amino acid indicate identical residues and highly conserved residues, respectively.

Figure 4.

CL biosynthesis (de‐novo) pathway and remodelling pathway. Tafazzin plays an important role of CoA‐independent transacylation between different phospholipids. CDP‐DAG, cytidinediphosphate‐diacylglycerol; MLCL AT‐1, monolysocardiolipin acyltransferase‐1; PC, phosphatidylcholine; PE, phosphatidylethanolamine and PLA2, phospholipase A2.



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Further Reading

Hauff KD and Hatch GM (2006) Cardiolipin metabolism and Barth Syndrome. Progress in Lipid Research 45: 91–101.

Houtkooper RH and Vaz FM (2008) Cardiolipin, the heart of mitochondrial metabolism. Cellular and Molecular Life Sciences 65: 2493–2506.

Xu Y, Malhotra A, Ren M et al. (2006) The enzymatic function of tafazzin. Journal of Biological Chemistry 281: 39217–39224.

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Takeda, Atsuhito(Sep 2013) Molecular Genetics of Barth Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025024]