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

Yu, Jialing; Liang, Xiaoyang; Ji, Yanchun; Ai, Cheng; Liu, Junxia; Zhu, Ling; Nie, Zhipeng; Jin, Xin; Wang, Chenghui; Zhang, Juanjuan; Zhao, Fuxin; Mei, Shuang; Zhao, Xiaoxu; Zhou, Xiangtian; Zhang, Minglian; Wang, Meng; Huang, Taosheng; Jiang, Pingping; Guan, Min‐Xin

doi:10.1172/jci134965

Cited by 50 publications

(55 citation statements)

References 70 publications

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“…To investigate whether the m.4295A>G mutation induced-alterations affected the stability of OXPHOS complexes, we measured the steady-state levels of five OXPHOS complexes by Blue-native polyacrylamide gel electrophoresis ( 58 , 66 , 67 ). As shown in Figure 7A and B , the levels of complex I (CI), complex III (CIII), complex IV (CIV) and complex V (CV) in the mutant cybrids were 45.94% ( P < 0.001), 82.08% ( P < 0.001), 68.79% ( P < 0.001) and 60.54% ( P < 0.001) of those in the control cybrids after normalization to TOM20, respectively.…”

Section: Resultsmentioning

confidence: 99%

A deafness-associated tRNA mutation caused pleiotropic effects on the m1G37 modification, processing, stability and aminoacylation of tRNAIle and mitochondrial translation

Meng

Zhou

Xiao

et al. 2021

Nucleic Acids Research

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Defects in the posttranscriptional modifications of mitochondrial tRNAs have been linked to human diseases, but their pathophysiology remains elusive. In this report, we investigated the molecular mechanism underlying a deafness-associated tRNAIle 4295A>G mutation affecting a highly conserved adenosine at position 37, 3′ adjacent to the tRNA’s anticodon. Primer extension and methylation activity assays revealed that the m.4295A>G mutation introduced a tRNA methyltransferase 5 (TRMT5)-catalyzed m1G37 modification of tRNAIle. Molecular dynamics simulations suggested that the m.4295A>G mutation affected tRNAIle structure and function, supported by increased melting temperature, conformational changes and instability of mutated tRNA. An in vitro processing experiment revealed that the m.4295A>G mutation reduced the 5′ end processing efficiency of tRNAIle precursors, catalyzed by RNase P. We demonstrated that cybrid cell lines carrying the m.4295A>G mutation exhibited significant alterations in aminoacylation and steady-state levels of tRNAIle. The aberrant tRNA metabolism resulted in the impairment of mitochondrial translation, respiratory deficiency, decreasing membrane potentials and ATP production, increasing production of reactive oxygen species and promoting autophagy. These demonstrated the pleiotropic effects of m.4295A>G mutation on tRNAIle and mitochondrial functions. Our findings highlighted the essential role of deficient posttranscriptional modifications in the structure and function of tRNA and their pathogenic consequence of deafness.

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Section: Resultsmentioning

confidence: 99%

A deafness-associated tRNA mutation caused pleiotropic effects on the m1G37 modification, processing, stability and aminoacylation of tRNAIle and mitochondrial translation

Meng

Zhou

Xiao

et al. 2021

Nucleic Acids Research

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“…It is predicted the hemizygosity of the X chromosome unmasks a high‐risk haplotype, resulting in digenic inheritance in LHON families. More than one X‐linked modifier region has been identified in this patient population (Yu et al, 2020). The inheritance pattern observed in Family 1 raises an intriguing hypothesis of a X‐linked haplotype increasing the likelihood of penetrance in males.…”

Section: Discussionmentioning

confidence: 93%

Mitochondrial genome variant m.3250T>C as a possible risk factor for mitochondrial cardiomyopathy

et al. 2020

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The MT-TL1 gene codes for the mitochondrial leucine transfer RNA (tRNA Leu(UUR)) necessary for mitochondrial translation. Pathogenic variants in the MT-TL1 gene result in mitochondriopathy in humans. The m.3250T>C variant in the MT-TL1 gene has been previously associated with exercise intolerance and mitochondrial myopathy, yet disease classification for this variant has not been consistently reported. Molecular studies suggest the m.3250T>C variant does not alter tRNA Leu(UUR) structure but may have a modest impact on aminoacylation capacity. However, functional studies are limited. Our study aimed to further define the clinical presentation, inheritance pattern, and molecular pathology of the m.3250T>C variant. Families with the m.3250T>C variant were recruited from the Mitochondrial Disease Clinic at Cincinnati Children's Hospital Medical Center and GeneDx laboratory database. Affected individuals most frequently presented with cardiac findings, exercise intolerance, and muscle weakness. Hypertrophic cardiomyopathy was the most frequent cardiac finding. Many asymptomatic individuals had homoplasmic or near homoplasmic levels of the m.3250T>C variant, suggesting the penetrance is incomplete. Patient-derived fibroblasts demonstrated lowered ATP production and increased levels of reactive oxygen species. Our results demonstrate that the m.3250T>C variant exhibits incomplete penetrance and may be a possible cause of cardiomyopathy by impacting cellular respiration in mitochondria.

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“…Moreover, incomplete penetrance and male bias in patients with LHON suggest that an X-linked modified gene is necessary for the disease expression ( Bu & Rotter, 1991 ). A recent genome-wide study of 1281 Chinese probands with LHON identified a novel LHON susceptibility allele (c.157C>T, p. Arg53Trp) in the PRICKLE3 gene, which links to ATPase biogenesis manifested LHON ( Yu et al, 2020 ). Moreover, a missense mutation in YARS2 (c.572G>T, p. Gly191Val) was shown to interact with the 11778G>A mutation to cause visual failure ( Jiang et al, 2016 ).…”

Section: Review Methodologymentioning

confidence: 99%

Leber’s Hereditary Optic Neuropathy: the roles of mitochondrial transfer RNA variants

Ding

Zhuo

Guo

et al. 2021

PeerJ

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Leber’s Hereditary Optic Neuropathy (LHON) was a common maternally inherited disease causing severe and permanent visual loss which mostly affects males. Three primary mitochondrial DNA (mtDNA) mutations, ND1 3460G>A, ND4 11778G>A and ND6 14484T>C, which affect genes encoding respiratory chain complex I subunit, are responsible for >90% of LHON cases worldwide. Families with maternally transmitted LHON show incomplete penetrance with a male preponderance for visual loss, suggesting the involvement of secondary mtDNA variants and other modifying factors. In particular, variants in mitochondrial tRNA (mt-tRNA) are important risk factors for LHON. These variants decreased the tRNA stability, prevent tRNA aminoacylation, influence the post-transcriptionalmodification and affect tRNA maturation. Failure of mt-tRNA metabolism subsequently impairs protein synthesis and expression, folding, and function of oxidative phosphorylation (OXPHOS) enzymes, which aggravates mitochondrial dysfunction that is involved in the progression and pathogenesis of LHON. This review summarizes the recent advances in our understanding of mt-tRNA biology and function, as well as the reported LHON-related mt-tRNA second variants; it also discusses the molecular mechanism behind the involvement of these variants in LHON.

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

Cited by 50 publications

References 70 publications

A deafness-associated tRNA mutation caused pleiotropic effects on the m1G37 modification, processing, stability and aminoacylation of tRNAIle and mitochondrial translation

A deafness-associated tRNA mutation caused pleiotropic effects on the m1G37 modification, processing, stability and aminoacylation of tRNAIle and mitochondrial translation

Mitochondrial genome variant m.3250T>C as a possible risk factor for mitochondrial cardiomyopathy

Leber’s Hereditary Optic Neuropathy: the roles of mitochondrial transfer RNA variants

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