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Identification of an ND4 Mutation in Leber Hereditary Optic Neuropathy

Lu, Qian MD1; Guo, Yi PhD1,2; Yi, Junhui PhD3; Deng, Xiong RA1; Yang, Zhijian RA1; Yuan, Xiuhong PhD4†; Deng, Hao PhD1*

doi: 10.1097/OPX.0000000000001147
Original Investigations

SIGNIFICANCE We identified a missense mutation, m.11778G>A (p.R340H), in the mitochondrially encoded NADH dehydrogenase 4 gene (ND4) in eight patients and three asymptomatic carriers, even though the incidence of this has been considered low in Chinese population. These results have implications for the families' genetic counseling and clinical management.

PURPOSE Leber hereditary optic neuropathy (LHON OMIM 535000) is one of the most common inherited optic neuropathies. The aim of this study was to identify the genetic cause in two Han Chinese families with LHON.

METHODS We used Sanger sequencing to identify the genetic cause of two Han Chinese families from Hunan, China, with LHON.

RESULTS The patients in these two families presented with typical LHON, with male patients experiencing more severe phenotypes. A missense mutation, m.11778G>A (p.R340H), in the ND4 gene was identified in eight patients and three asymptomatic carriers, even though the incidence of this has been considered low in Chinese population.

CONCLUSIONS Eight of 11 family members (72.7%) manifested some vision loss, which is far higher percentage than reported in other studies. The variant is predicted to be the disease-causing mutation and results in seriously abnormal function of complex I subunits of the mitochondrial respiratory chain. These results have implications for the families' genetic counseling and clinical management and help to develop new LHON target-gene therapy strategies.

1Center for Experimental Medicine and Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China

2Department of Medical Information, Information Security and Big Data Research Institute, Central South University, Changsha, China

3Department of Ophthalmology, the Third Xiangya Hospital, Central South University, Changsha, China

4Department of Clinical Psychology, the Third Xiangya Hospital, Central South University, Changsha, ChinaQL and YG contributed equally to this article. *hdeng008@yahoo.com; †zm5310@sohu.com

Submitted: December 12, 2016

Accepted: August 29, 2017

Funding/Support: This work was supported by grants from National Key Research and Development Program of China (2016YFC1306604), National Natural Science Foundation of China (81271921 and 81670216), Natural Science Foundation of Hunan Province (2015JJ4088 and 2016JJ2166), Grant for the Foster Key Subject of the Third Xiangya Hospital Clinical Laboratory Diagnostics (to HD), Zhishan Lead Project of the Third Xiangya Hospital (to HD).

Conflict of Interest Disclosure: None of the authors have reported a conflict of interest.

Author Contributions and Acknowledgments: Conceptualization, Data Curation, Writing – Original Draft: QL; Data Curation, Formal Analysis, Methodology, Software: YG; Formal Analysis and Investigation: JY; Methodology and Software: XD; Investigation and Methodology: ZY; Project Administration, Supervision, Validation, Visualization: XY; Conceptualization, Resources, Supervision, Writing – Review & Editing: HD.

The authors thank all the participating patients and investigators for their contributions to this research.

© 2017 American Academy of Optometry