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

The Journal of Clinical Investigation
Jialing YuMin-Xin Guan

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-...Continue Reading

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Citations

Jul 30, 2020·The Journal of Biological Chemistry·Yanchun JiMin-Xin Guan
Nov 8, 2020·Drugs·Giulia AmoreChiara La Morgia
Mar 4, 2021·FEBS Letters·Mirjana Gusic, Holger Prokisch
May 24, 2021·The Journal of Biological Chemistry·Yanchun JiMin-Xin Guan
Jun 23, 2021·Investigative Ophthalmology & Visual Science·Xiaofen JinMin-Xin Guan
Jul 16, 2021·The Journal of Biological Chemistry·Qiufen HeMin-Xin Guan
Jun 2, 2021·Seminars in Cell & Developmental Biology·Lingling WangC Yan Cheng

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Datasets Mentioned

BETA
PRJNA634625
HY-128974

Methods Mentioned

BETA
electrophoresis
immunoprecipitation assay
genotyping
PCR
immunoprecipitation
transfection
Assay

Software Mentioned

Mitoprot
GraphPad Prism
UCSC Genome Browser
Nikon NIS - Elements
SOAPsnp

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