A novel mutation in the G4.5 (TAZ) gene in a Greek patient with Barth syndrome

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Abstract

Barth Syndrome (BTHS) is a rare X-linked recessive inborn error of metabolism, which is characterized by dilated cardiomyopathy, neutropenia, skeletal myopathy and short stature. Barth Syndrome is associated with mutations in the tafazzin (TAZ) gene at Xq28 that result in cardiolipin deficiency and abnormal mitochondria. Here we report a 5.5-month old boy with BTHS phenotype who carries a novel missense T43P mutation in exon 2 of the TAZ gene.

Introduction

Barth Syndrome (BTHS MIM302060) or cardioskeletal myopathy with neutropenia, firstly described by Barth et al., in 1983 [1], is an X-linked recessive disorder which is typically characterized by cardiomyopathy, neutropenia, skeletal myopathy, growth delay and elevated urinary excretion of 3-methylglutarate, 3-methylglutaconate and 2-ethyldracrylate. Hypocholesterolemia is also included in the biochemical abnormalities although it is not always present [2], [3].

Various mutations of the TAZ gene, which is located in the Xp28 [4], [5], [6] region, have been associated with Barth Syndrome, as well as other types of X-linked cardiomyopathies such as X-linked endocardial fibroelastosis, severe X-linked cardiomyopathy and isolated left ventricular non compaction (ILVNC) [7], [8], [9], [10].

Disease causing mutations have been reported in all 11 exons of the TAZ gene [11], [12]. This gene encodes taffazins, proteins with phospholipid acyltransferase function and seem to have an important role in the remodeling of cardiolipin and phosphatidylglycerol [13], [14], [15], [16]. Cardiolipin is a component of the inner mitochondrial membrane, the loss of which leads to the loss of cytochrome-C into the cytosol and represents a crucial step in cellular apoptosis [17]. Tafazzin, is conserved during evolution, suggesting a functionally important role during fetal and neonatal life [11]. To date, 28 different mutations resulting in single amino-acid changes in the Taz protein have been identified in BTHS patients. Aside from mutations resulting in either complete loss of Taz protein expression or expression of a severely truncated Taz, a biochemical explanation for the defect associated with any identified BTHS point mutation has not been provided.

In the present study, a novel mutation in exon 2 of the Taz gene was identified in a Greek patient with Barth syndrome.

Section snippets

Case report

A 5.5 month old male infant presented with growth delay, cyanosis, perspiration during feeding and diarrhea since the age of 3 months. Physical examination revealed tachypnea, tachycardia and a soft murmur at the left sternal border and the cardial apex. In the electrocardiogram LV hypertrophy with strain was found. Echocardiography revealed a seriously dilated left ventricle with impaired systolic function (SF: 15%, LV EF:42.2%), mitral regurgitation due to dilation, deep endomyocardial

Materials and methods

Genomic DNA was extracted from peripheral blood leukocytes. The exon 2 coding region of TAZ gene was amplified by PCR, as previously described (Ichida et al. 2001) using the primers: forward 5′-ACCTAGCGGGCGAGCCCGGA-3′ and reverse 5′-TTTCCTCCCCCTGCCCAG CA-3′. Direct sequencing was then performed according to the Visible Genetics 7-Deaza-dGTP-CyTM5/Cy5.5. Dye Primer Cycle Sequencing Kit protocol and analyzed on Visible Genetics OpenRead Tower.

Results and discussion

In this patient we found an A-to-C substitution within exon 2 in a hemizygous pattern, resulting in the replacement of threonine with proline (Thr43Pro). The Thr43Pro mutation was also found in his mother (heterozygous). Father, as well as maternal grandparents, were not carriers of the mutation (Fig. 1). Consequently this mutation was considered a de novo mutation in the mother (heterozygous) which was transmitted to her son (hemizygous) who carries only the mutated allele of TAZ gene. The

Acknowledgments

This study was supported by the University of Athens, SARG grant no 70/4/4256 (A.K.). The authors would like to thank Dr C. Sofocleous (Dept of Medical Genetics, University of Athens) and Drs R.H. Lekanne dit Deprez and M.M.A.M Mannens (Dept of Clinical Gentics, AMC University of Amsterdam) for their contribution in molecular analysis.

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