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

doi: 10.1007/8904_2013_228. Epub 2013 Apr 19.

Jon Steller, Iris L Gonzalez, Wim Kulik, Michelle Fox, Richard Chang, Brandy A Westerfield, Anjan S Batra, Raymond Yu Jeang Wang, Natalie M Gallant, Liana S Pena, Hu Wang, Taosheng Huang, Sunita Bhuta, Daniel J Penny, Edward R McCabe, Virginia E Kimonis

Affiliations

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

Yuxin Fan et al. JIMD Rep. 2013.

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.

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Figures

Fig. 1

Fig. 1

An echocardiogram displaying severe left ventricular and atrial dilation. LA left atrium, LV left ventricle, RA right atrium, RV right ventricle

Fig. 2

Fig. 2

Cross sections from the 64.0 g explanted heart exhibit prominent trabeculations involving greater than 50% of the left ventricular wall thickness. Also note thickened fibroelastotic endocardium

Fig. 3

Fig. 3

Hematoxylin- and eosin-stained section of left ventricle shows hypertrophic cardiac myocytes (x10)

Fig. 4

Fig. 4

This photomicrograph shows significantly thickened endocardium with duplication of elastic fibers (red) and collagen fibers (blue) highlighted with Trichrome-EVG stain (Elastic Van Gieson Stain). (x10). In general, the normal endocardium has fewer than five layers of elastic fibers

Fig. 5

Fig. 5

(a) Noticeable onion skinning of the mitochondrial cristae, fusion of intracristae inner mitochondrial membrane preventing transport, and marked variation in size of mitochondria. (b) Note many inclusions of glycogen in intramitochondrial vacuoles replacing sarcomeres. (c, d) Notice disorganized stacks of cristae, intramitochondrial glycogen, and glycogen surrounding mitochondria

Fig. 6

Fig. 6

A pedigree of our family with atypical Barth syndrome. Filled symbols indicate clinically affected individuals; open symbols indicate unaffected individuals; a slash through a circle or square indicates a deceased individual; symbol with “?” indicates an individual who did not have clinical evaluation and genetic testing; squares indicate males; circles indicate females. The proband patient is marked with an arrow

Fig. 7

Fig. 7

TAZ sequencing of the family members revealed that the proband’s mother, maternal aunt, and grandmother all carry the c.553A>G substitution

Fig. 8

Fig. 8

(Top) TAZ gene diagram showing mutation location and its effect on splicing. (Bottom) Processed mRNA including complete intron 6 retention and only 11 bases of exon 7

Fig. 9

Fig. 9

MLCL and CL analysis performed on patient lymphoblast cell line shows the monolysocardiolipin and cardiolipin profiles with their characteristic doubly charged ions. The ratio of monolysocardiolipin/cardiolipin species is strongly increased as compared to normal controls (see Houtkooper et al. 2009). m/z mass/charge

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