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

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 the PRICKLE3 encoding a mitochondrial protein linked to biogenesis of ATPase in three Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only single mutation exhibited normal vision. The cells carrying the p.Arg53Trp mutation exhibited the defective assembly, stability and function of ATP synthase, verified by PRICKLE3 knock-down cells. Co-immunoprecipitation indicated the direct interaction of PRICKLE3 with ATP synthase via ATP8. Strikingly, mutant cells bearing both p.Arg53Trp and m.11778G>A mutations displayed greater mitochondrial dysfunctions than those carrying only single mutation. These indicated that the p.Arg53Trp mutation acted in synergy with m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON. Furthermore, we demonstrated that Prickle3 deficient mice exhibited the pronounced ATPase deficiencies. Prickle3 knock-out mice recapitulated LHON phenotypes with retina deficiencies including degeneration of retinal ganglion cells and abnormal vasculature. Our findings provided new insights into pathophysiology of LHON that were manifested by interaction between mtDNA mutation and X-linked nuclear modifier.