Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya diseaseResearch in context
Chia-Yi Li,
Li-Wen Chen,
Meng-Che Tsai,
Yen-Yin Chou,
Pei-Xuan Lin,
Yu-Ming Chang,
Wuh-Liang Hwu,
Yin-Hsiu Chien,
Ju-Li Lin,
Hui-An Chen,
Ni-Chung Lee,
Pen-Hua Su,
Tzung-Chien Hsieh,
Hannah Klinkhammer,
Yi-Chieh Wang,
Yi-Ting Huang,
Peter M. Krawitz,
Sheng-Hsiang Lin,
Lynn L.H. Huang,
Po-Min Chiang,
Min-Hsiu Shih,
Peng-Chieh Chen
Affiliations
Chia-Yi Li
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Li-Wen Chen
Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Meng-Che Tsai
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Genomic Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Yen-Yin Chou
Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Genomic Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Pei-Xuan Lin
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Yu-Ming Chang
Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Wuh-Liang Hwu
Precision Medical Center, China Medical University Hospital, Taichung City, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
Yin-Hsiu Chien
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
Ju-Li Lin
Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan
Hui-An Chen
Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
Ni-Chung Lee
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
Pen-Hua Su
Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
Tzung-Chien Hsieh
Institute for Genomic Statistics and Bioinformatics, Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
Hannah Klinkhammer
Institute for Genomic Statistics and Bioinformatics, Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany; Institute for Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
Yi-Chieh Wang
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Yi-Ting Huang
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Peter M. Krawitz
Institute for Genomic Statistics and Bioinformatics, Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
Sheng-Hsiang Lin
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Lynn L.H. Huang
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan
Po-Min Chiang
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Min-Hsiu Shih
Department of Ophthalmology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Peng-Chieh Chen
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Corresponding author. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Summary: Background: Impaired mitochondrial protein import machinery leads to phenotypically heterogeneous diseases. Here, we report a recurrent homozygous missense variant in the gene that encodes the translocase of outer mitochondrial membrane 7 (TOMM7) in nine patients with microcephaly, short stature, facial dysmorphia, atrophic macular scarring, and moyamoya disease from seven unrelated families. Methods: To prove the causality of the TOMM7 variant, mitochondrial morphology, proteomics, and respiration were investigated in CRISPR/Cas9-edited iPSCs-derived endothelial cells. Cerebrovascular defects and mitochondrial respiration were also examined in CRISPR/Cas9-edited zebrafish. Findings: iPSC-derived endothelial cells with homozygous TOMM7 p.P29L showed increased TOM7 stability, enlarged mitochondria, increased senescence, and defective tube formation. In addition, proteomic analysis revealed a reduced abundance of mitochondrial proteins involved in ATP synthesis or coordinating TCA cycle and gluconeogenesis. Moreover, mitochondrial respiration was slightly decreased while ATP production from glycolysis was significantly increased. Furthermore, deletion of tomm7 in zebrafish caused craniofacial and cerebrovascular defects that recapitulated human phenotypes. Notably, homozygous iPSCs differentially expressed genes involved in glycolysis and response to hypoxia. Finally, the metabolic imbalance was evidenced by decreased oxygen consumption, increased level of hexokinase 2, and enhanced glycolysis in endothelial cells derived from the patient's iPSCs. Interpretation: These results revealed the essential role of TOMM7 in balancing cellular sources of energy production at both proteomic and transcriptomic levels and provided the molecular mechanisms through which TOMM7 p.P29L variant leads to an autosomal recessive microcephalic osteodysplastic dwarfism with moyamoya disease. Funding: This work is supported by National Science and Technology Council grants and National Cheng Kung University Hospital.
