title: A novel mutation in TAZ causes mitochondrial respiratory chain disorder without cardiomyopathy.
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.
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Nurun N
authors.initials: NN
authors.lastname: Borna
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kishita
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakada
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Hayashi
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Tokuzawa
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Masakazu
authors.identifier: http://orcid.org/0000-0001-5970-2224
authors.initials: M
authors.lastname: Kohda
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nyuzuki
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Yzumi
authors.initials: Y
authors.lastname: Yamashita-Sugahara
authors.affiliation: Department of Pediatrics, Obihiro Kosei General Hospital, Obihiro, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nasu
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Takeda
authors.affiliation: Department of Metabolism, Chiba Children's Hospital, Chiba, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Murayama
authors.affiliation: Department of Pediatrics, Saitama Medical University, Saitama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.|Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
mesh_terms: D000217:Acyltransferases; D001483:Base Sequence; D009202:Cardiomyopathies / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004579:Electron Transport / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011247:Pregnancy; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D014157:Transcription Factors; D000217:Acyltransferases; C108675:TAFAZZIN protein, human