2. Academic Validation
  3. PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy

PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy

  • J Clin Invest. 2020 Sep 1;130(9):4935-4946. doi: 10.1172/JCI134965.
Jialing Yu 1 2 3 4,  Xiaoyang Liang 2 3,  Yanchun Ji 1 2 3,  Cheng Ai 2 3,  Junxia Liu 2 3,  Ling Zhu 1 2 3,  Zhipeng Nie 2 3,  Xiaofen Jin 2 3 4,  Chenghui Wang 2 3,  Juanjuan Zhang 2 5,  Fuxin Zhao 5,  Shuang Mei 2 3,  Xiaoxu Zhao 1 2 3,  Xiangtian Zhou 5,  Minglian Zhang 6,  Meng Wang 1 2 3,  Taosheng Huang 7,  Pingping Jiang 1 2 3,  Min-Xin Guan 1 2 3 4 8
Affiliations

Affiliations

  • 1 Division of Medical Genetics and Genomics, Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, China.
  • 2 Institute of Genetics and.
  • 3 Department of Human Genetics, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Key Laboratory of Reproductive Genetics, Ministry of Education, Hangzhou, China.
  • 5 School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.
  • 6 Department of Ophthalmology, Hebei Provincial Eye Hospital, Xingtai, China.
  • 7 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • 8 Joint Institute of Genetics and Genomic Medicine, Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, China.
PMID: 32516135 DOI: 10.1172/JCI134965
Abstract

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease. X-linked nuclear modifiers were proposed to modify the phenotypic manifestation of LHON-associated mitochondrial DNA (mtDNA) mutations. By whole-exome Sequencing, we identified the X-linked LHON modifier (c.157C>T, p.Arg53Trp) in PRICKLE3 encoding a mitochondrial protein linked to biogenesis of ATPase in 3 Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only a single mutation exhibited normal vision. The cells carrying the p.Arg53Trp mutation exhibited defective assembly, stability, and function of ATP Synthase, verified by PRICKLE3-knockdown cells. Coimmunoprecipitation indicated the direct interaction of PRICKLE3 with ATP Synthase via ATP8. Strikingly, cells bearing both p.Arg53Trp and m.11778G>A mutations displayed greater mitochondrial dysfunction than those carrying only a single mutation. This finding indicated that the p.Arg53Trp mutation acted in synergy with the m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON. Furthermore, we demonstrated that Prickle3-deficient mice exhibited pronounced ATPase deficiencies. Prickle3-knockout mice recapitulated LHON phenotypes with retinal deficiencies, including degeneration of retinal ganglion cells and abnormal vasculature. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutations and X-linked nuclear modifiers.

Keywords

Genetic diseases; Genetics; Mitochondria; Molecular pathology; Ophthalmology.

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