The mitochondrial tRNAThr A15951G mutation may influence the phenotypic expression of the LHON-associated ND4 G11778A mutation in a Chinese family

Li, Ronghua; Qu, Jia; Zhou, Xiangtian; Tong, Yi; Hu, Yu‐Chen; Qian, Yaping; Liu, Fan; Mo, Jun Qin; West, Constance E.; Guan, Min‐Xin

doi:10.1016/j.gene.2006.02.014

Cited by 59 publications

(58 citation statements)

References 36 publications

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“…The average age-at-onset for visual loss in matrilineal relatives of this family, as shown in Table 3, is comparable with those in other families carrying the G11778A mutation (Harding et al 1995;Newman et al 1991;Qu et al 2005;Qian et al 2005;Qu et al 2006;. Furthermore, the ratio between affected male and female matrilineal relatives is 3.5:1 in this Chinese family in the present study, while the ratios were 1:1, 1.2:1, 2:1, 3:0, 3:1 and 6:0 in other six Chinese families Qian et al 2005;Qu et al 2006;Li et al 2006). However, this ratio was 4.5:1 and 3.7:1 from two large cohorts of Caucasian pedigrees carrying the G11778A mutation, respectively (Newman et al 1991;Harding et al 1995).…”

Section: Discussionsupporting

confidence: 88%

“…In particular, the tRNA Met A4435G and tRNA Thr A15951G mutations were implicated to play a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in two Han Chinese families Li et al 2006). Furthermore, we showed that five Chinese families with extremely low penetrances of LHON were associated with the ND4 G11696A mutation .…”

Section: Introductionmentioning

confidence: 66%

“…In particular, G7444A mutation in the CO1 and tRNA Ser(UCN) genes was implicated to influence the penetrance and phenotypic expression of visual loss associated with the primary LHONassociated mtDNA mutations (Brown et al 1995) and hearing loss associated with the mtDNA A1555G mutation (Yuan et al 2005). Most recently, we showed that the tRNA Met A4435G and tRNA Thr A15951G mutations have a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in Chinese families Li et al 2006). In this Chinese family, there were other 33 variants including the G11696A mutation in the mtDNA belonging to the Eastern Asian haplogroup D4 (Tanaka et al 2004).…”

Section: Discussionmentioning

confidence: 93%

“…However, this ratio was 4.5:1 and 3.7:1 from two large cohorts of Caucasian pedigrees carrying the G11778A mutation, respectively (Newman et al 1991;Harding et al 1995). In addition, 33% of matrilineal relatives in this Chinese family developed visual loss, in contrast with the fact that only 16, 33, 36, 36 57 and 60% of matrilineal relatives developed visual loss in other six Chinese families Qian et al 2005;Qu et al 2006;Li et al 2006). However, ~50% males and ~10% females in Caucasians carrying one of LOHN associated G3460A, G11778A and T14484C mutations indeed developed the optic neuropathy (Nikoskekainen 1994;Brown and Wallace 1994).…”

Section: Discussionmentioning

confidence: 94%

“…With the aim of investigating the role of mitochondrial halpotypes in the phenotypic expression of LHON, a systematic and extended mutational screening of mtDNA has been initiated in the large clinical population of Ophthalmology Clinic at the Wenzhou Medical College, China Qu et al 2005;Qu et al 2006;Li et al 2006). In particular, the tRNA Met A4435G and tRNA Thr A15951G mutations were implicated to play a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in two Han Chinese families Li et al 2006).…”

Section: Introductionmentioning

confidence: 99%

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Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family

Zhou

et al. 2007

Mitochondrion

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We report here the characterization of a four-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON). This Chinese family exhibited a variable severity and age-at-onset of visual loss. Notably, the average age-at-onset of vision impairment changed from 26 years (generation III) to 14 years (generation IV), with the average of 18 years in this family. In addition, 30% and 50% of matrilineal relatives in generation III and IV of this family developed visual loss with a variability of severity, ranging from blindness to normal vision. Sequence analysis of the complete mitochondrial DNA in this pedigree revealed the presence of the homoplasmic ND4 G11778A mutation and 33 other variants, belonging to the Asian haplogroup D4. Of other variants, the homoplasmic G11696A mutation in the ND4 gene is of special interest as it was implicated to be associated with LHON in a large Dutch family and five Chinese pedigrees with extremely penetrance of visual loss. In fact, the G11696A mutation caused the substitution of an isoleucine for valine at amino acid position 313, located in a predicted transmembrane region of ND4. These imply that the G11696A mutation may act in synergy with the primary LHON-associated G11778A mutation in this Chinese pedigree.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family

Zhou

et al. 2007

Mitochondrion

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Mitochondrial tRNA^Glu 14693A > G Mutation, an “Enhancer” to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy

Jin,

Gan,

et al. 2024

Advanced Science

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Leber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNAGlu 14693A > G and ND6 14484T > C mutations in three Chinese families affected by LHON is investigated. The m.14693A > G mutation nearly abolishes the pseudouridinylation at position 55 of tRNAGlu, leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the ND6 14484T > C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual‐mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.

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Mitochondria: a hub of redox activities and cellular distress control

2007

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In their reductionist approach in unraveling phenomena inside the cell, scientists in recent times have focused attention to mitochondria. An organelle with peculiar evolutionary history and organization, it is turning out to be an important cell survival switch. Besides controlling bioenergetics of a cell it also has its own genetic machinery which codes 37 genes. It is a major source of generation of reactive oxygen species, acts as a safety device against toxic increases of cytosolic Ca2+ and its membrane permeability transition is a critical control point in cell death. Redox status of mitochondria is important in combating oxidative stress and maintaining membrane permeability. Importance of mitochondria in deciding the response of cell to multiplicity of physiological and genetic stresses, inter-organelle communication, and ultimate cell survival is constantly being unraveled and discussed in this review. Mitochondrial events involved in apoptosis and necrotic cell death, such as activation of Bcl-2 family proteins, formation of permeability transition pore, release of cytochrome c and apoptosis inducing factors, activation of caspase cascade, and ultimate cell death is the focus of attention not only for cell biologists, but also for toxicologists in unraveling stress responses. Mutations caused by ROS to mitochondrial DNA, its inability to repair it completely and creation of a vicious cycle of mutations along with role of Bcl-2 family genes and proteins has been implicated in many diseases where mitochondrial dysfunctions play a key role. New therapeutic approaches toward targeting low molecular weight compounds to mitochondria, including antioxidants is a step toward nipping the stress in the bud.

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The mitochondrial tRNAThr A15951G mutation may influence the phenotypic expression of the LHON-associated ND4 G11778A mutation in a Chinese family

Cited by 59 publications

References 36 publications

Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family

Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family

Mitochondrial tRNA^Glu 14693A > G Mutation, an “Enhancer” to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy

Mitochondria: a hub of redox activities and cellular distress control

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The mitochondrial tRNAThr A15951G mutation may influence the phenotypic expression of the LHON-associated ND4 G11778A mutation in a Chinese family

Cited by 59 publications

References 36 publications

Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family

Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family

Mitochondrial tRNAGlu 14693A > G Mutation, an “Enhancer” to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy

Mitochondria: a hub of redox activities and cellular distress control

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Product

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Mitochondrial tRNA^Glu 14693A > G Mutation, an “Enhancer” to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy