Abstract
Tafazzin, encoded by the TAZ gene, is a mitochondrial membrane-associated protein that remodels cardiolipin (CL), an important mitochondrial phospholipid. TAZ mutations are associated with Barth syndrome (BTHS). BTHS is an X-linked multisystemic disorder affecting usually male patients. Through sequence analysis of TAZ, we found one novel mutation c.39_60del p.(Pro14Alafs*19) by whole-exome sequencing and a reported missense mutation c.280C>T p.(Arg94Cys) by Sanger sequencing in two male patients (Pt1 and Pt2). Patient with c.280C>T mutation had dilated cardiomyopathy, while another patient with c.39_60del mutation had no feature of cardiomyopathy. A reported m.1555A>G homoplasmic variant was also identified in the patient having mutation c.39_60del by whole mitochondrial DNA sequencing method. This variant was not considered to be the main cause of mitochondrial dysfunction based on a cytoplasmic hybrid (cybrid) assay. Tafazzin expression was absent in both patient-derived fibroblast cells. Complementation of TAZ expression in fibroblasts from the patient with the novel mutation c.39_60del restored mitochondrial respiratory complex assembly. High-performance liquid chromatography–tandem mass spectrometry-based metabolic analysis revealed the decline of CL and the accumulation of monolysocardiolipin, indicating the loss of tafazzin activity. Owing to phenotypic variability, it is difficult to diagnose BTHS based on clinical features only. We conclude that genetic analysis should be performed to avoid underdiagnosis of this potentially life-threatening inborn error of metabolism.
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Acknowledgements
This work was supported by a grant of the Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan to YO; the Support Project and a grant of Strategic Research Center in Private Universities from the MEXT, Japan to Saitama Medical University Research Center for Genomic Medicine. This work was also supported by Grants-in-Aid of the Research on Intractable Diseases (Mitochondrial Disorder) from the Ministry of Health, Labor and Welfare of Japan to KM. YO received a Special research grant from Takeda Science Foundation. NNB is a recipient of the Saitama Medical University Research Fellowship. We acknowledge the Laboratory Genetic Metabolic Disease in the Academic Medical Center in Amsterdam for measuring the MLCL/CL ratio. We thank Atsuko Imai for providing valuable comments. We are grateful to Ryoko Nakamura, Department of Pediatric Neurology, Fukuoka Children’s Hospital, Fukuoka, Japan; who is an attending physician of one of our patients.
Author contributions
NNB, YK and YO designed the study. NNB, YK and KI acquired data. KN, J-IH, YT, MK, HN, YY-S, KM and AO gave critical comments. YO, NNB and YK wrote the manuscript.
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Borna, N., Kishita, Y., Ishikawa, K. et al. A novel mutation in TAZ causes mitochondrial respiratory chain disorder without cardiomyopathy. J Hum Genet 62, 539–547 (2017). https://doi.org/10.1038/jhg.2016.165
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DOI: https://doi.org/10.1038/jhg.2016.165
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