Hong Ren1, Yan Lin1, Ying Li2,3, Xiufang Zhang1, Wei Wang1, Xuebi Xu4, Kunqian Ji5, Yuying Zhao1, Chuanzhu Yan1,6,7. 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. 2. Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China. 3. Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China. 4. Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Nanbaixiang Street, Wenzhou, 325000, China. 421147343@qq.com. 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. jikunqian@email.sdu.edu.cn. 6. Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, 266035, Shandong, China. 7. Brain Science Research Institute, Shandong University, Jinan, 250000, Shandong, China.
Abstract
BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a common mitochondrial disease. More than 30 variants in the mitochondrial DNA (mtDNA) have been previously described in LHON. However, the pathogenicity of some variants remains unclear. Herein, we report a 19-year-old boy presenting unique LHON plus dystonia syndrome with the rare m.4136A > G and m.4160 T > C variants and elucidate the molecular pathomechanisms of the m.4160 T > C mutation. METHODS: We performed clinical, molecular genetic analysis, and biochemical investigation in the patient's different tissues and cybrid cell lines. RESULTS: The optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) of the patient showed typical pathological changes-a significant decrease in the 17 thickness of the retinal nerve fiber layer (RNFL) and the ganglion cell complex (GCC). Brain magnetic resonance imaging (MRI) found noteworthy abnormal signals in the basal ganglia region. The genetic analysis revealed that the m.4160 T > C variant was heteroplasmic in the blood (80.2%), urine sediment (90.8%), and oral mucosal (81.7%) samples of the patient. In contrast, the m.4136A > G variant was homoplasmic in all available tissues. Biochemical and bioenergetic investigations showed decreased mitochondrial protein levels and mitochondrial respiration deficiency in cybrid cells harboring these variants. CONCLUSIONS: This research provided more comprehensive data to help gain insight into the pathogenicity of the m.4160 T > C variant and broaden our view on the LHON plus phenotype.
BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a common mitochondrial disease. More than 30 variants in the mitochondrial DNA (mtDNA) have been previously described in LHON. However, the pathogenicity of some variants remains unclear. Herein, we report a 19-year-old boy presenting unique LHON plus dystonia syndrome with the rare m.4136A > G and m.4160 T > C variants and elucidate the molecular pathomechanisms of the m.4160 T > C mutation. METHODS: We performed clinical, molecular genetic analysis, and biochemical investigation in the patient's different tissues and cybrid cell lines. RESULTS: The optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) of the patient showed typical pathological changes-a significant decrease in the 17 thickness of the retinal nerve fiber layer (RNFL) and the ganglion cell complex (GCC). Brain magnetic resonance imaging (MRI) found noteworthy abnormal signals in the basal ganglia region. The genetic analysis revealed that the m.4160 T > C variant was heteroplasmic in the blood (80.2%), urine sediment (90.8%), and oral mucosal (81.7%) samples of the patient. In contrast, the m.4136A > G variant was homoplasmic in all available tissues. Biochemical and bioenergetic investigations showed decreased mitochondrial protein levels and mitochondrial respiration deficiency in cybrid cells harboring these variants. CONCLUSIONS: This research provided more comprehensive data to help gain insight into the pathogenicity of the m.4160 T > C variant and broaden our view on the LHON plus phenotype.
Authors: Elizna M van der Walt; Izelle Smuts; Robert W Taylor; Joanna L Elson; Douglass M Turnbull; Roan Louw; Francois H van der Westhuizen Journal: Eur J Hum Genet Date: 2012-01-18 Impact factor: 4.246