Kunqian Ji1, Chuanzhu Yan2,3,4, Yan Lin5, Jixiang Du5, Wei Wang5, Hong Ren5, Dandan Zhao5, Fuchen Liu5, Pengfei Lin5, Yuying Zhao5. 1. Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, 250012, Shandong, China. jikunqian@qq.com. 2. Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, 250012, Shandong, China. czyan@sdu.edu.cn. 3. Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, 266035, Shandong, China. czyan@sdu.edu.cn. 4. Brain Science Research Institute, Shandong University, Jinan, 250012, Shandong, China. czyan@sdu.edu.cn. 5. Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, 250012, Shandong, China.
Abstract
BACKGROUND: Mitochondrial disorders are clinically heterogeneous diseases associated with impaired oxidative phosphorylation (OXPHOS) activity. POLG, which encodes the DNA polymerase-γ (Polγ) catalytic subunit, is the most commonly mutated nuclear gene associated with mitochondrial disorders. METHODS: We carried out whole-exome sequencing (WES) to identify the gene associated with progressive external ophthalmoplegia (PEO). We then performed histopathological analyses, assessed mitochondrial biology, and executed functional studies to evaluate the potential pathogenicity of the identified genetic mutations. RESULTS: Novel biallelic POLG mutations, including a large deletion mutation (exons 7-21) and a missense variant c.1796C>T (p.Thr599Ile) were detected in the proband. Histopathological analysis of a biopsied muscle sample from this patient revealed the presence of approximately 20% COX-negative fibers. Bioinformatics analyses confirmed that the detected mutations were pathogenic. Furthermore, levels of mitochondrial complex I, II, and IV subunit protein expressions were found to be decreased in the proband, and marked impairment of mitochondrial respiration was evident in cells harboring these mutations. CONCLUSION: This study expands the spectrum of known POLG variants associated with PEO and advances current understanding regarding the structural and functional impacts of these mutations.
BACKGROUND: Mitochondrial disorders are clinically heterogeneous diseases associated with impaired oxidative phosphorylation (OXPHOS) activity. POLG, which encodes the DNA polymerase-γ (Polγ) catalytic subunit, is the most commonly mutated nuclear gene associated with mitochondrial disorders. METHODS: We carried out whole-exome sequencing (WES) to identify the gene associated with progressive external ophthalmoplegia (PEO). We then performed histopathological analyses, assessed mitochondrial biology, and executed functional studies to evaluate the potential pathogenicity of the identified genetic mutations. RESULTS: Novel biallelic POLG mutations, including a large deletion mutation (exons 7-21) and a missense variant c.1796C>T (p.Thr599Ile) were detected in the proband. Histopathological analysis of a biopsied muscle sample from this patient revealed the presence of approximately 20% COX-negative fibers. Bioinformatics analyses confirmed that the detected mutations were pathogenic. Furthermore, levels of mitochondrial complex I, II, and IV subunit protein expressions were found to be decreased in the proband, and marked impairment of mitochondrial respiration was evident in cells harboring these mutations. CONCLUSION: This study expands the spectrum of known POLG variants associated with PEO and advances current understanding regarding the structural and functional impacts of these mutations.
Authors: Sara Roos; Bertil Macao; Javier Miralles Fusté; Christopher Lindberg; Elisabeth Jemt; Elisabeth Holme; Ali-Reza Moslemi; Anders Oldfors; Maria Falkenberg Journal: Hum Mol Genet Date: 2013-02-27 Impact factor: 6.150
Authors: Gráinne S Gorman; Andrew M Schaefer; Yi Ng; Nicholas Gomez; Emma L Blakely; Charlotte L Alston; Catherine Feeney; Rita Horvath; Patrick Yu-Wai-Man; Patrick F Chinnery; Robert W Taylor; Douglass M Turnbull; Robert McFarland Journal: Ann Neurol Date: 2015-03-28 Impact factor: 10.422