A novel mitochondrial MTND5 frameshift mutation causing isolated complex I deficiency, renal failure and myopathy

Alston, Charlotte L.; Morak, Monika; Reid, Christopher; Hargreaves, Iain P.; Pope, Simon; Land, John M.; Heales, Simon; Horvath, Rita; Mundy, Helen; Taylor, Robert W.

doi:10.1016/j.nmd.2009.10.010

Cited by 31 publications

(21 citation statements)

References 23 publications

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“…Among them, both 10952insC and 11032–11038delA have been detected in renal oncocytoma [26], and 11032-11038delA was also found in prostate cancer [27]. The 12425delA has been previously identified in a girl having chronic renal failure, persistent lactic acidosis and myopathy [28]. A similar variation 12425insA has been reported in several cancers in a heteroplasmic status [29,30].…”

Section: Discussionmentioning

confidence: 77%

A Comprehensive Characterization of Mitochondrial Genome in Papillary Thyroid Cancer

Wang

Ruan

et al. 2016

IJMS

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Nuclear genetic alterations have been widely investigated in papillary thyroid cancer (PTC), however, the characteristics of the mitochondrial genome remain uncertain. We sequenced the entire mitochondrial genome of 66 PTCs, 16 normal thyroid tissues and 376 blood samples of healthy individuals. There were 2508 variations (543 sites) detected in PTCs, among which 33 variations were novel. Nearly half of the PTCs (31/66) had heteroplasmic variations. Among the 31 PTCs, 28 specimens harbored a total of 52 somatic mutations distributed in 44 sites. Thirty-three variations including seven nonsense, 11 frameshift and 15 non-synonymous variations selected by bioinformatic software were regarded as pathogenic. These 33 pathogenic mutations were associated with older age (p = 0.0176) and advanced tumor stage (p = 0.0218). In addition, they tended to be novel (p = 0.0003), heteroplasmic (p = 0.0343) and somatic (p = 0.0018). The mtDNA copy number increased in more than two-third (46/66) of PTCs, and the average content in tumors was nearly four times higher than that in adjacent normal tissues (p < 0.0001). Three sub-haplogroups of N (A4, B4a and B4g) and eight single-nucleotide polymorphisms (mtSNPs) (A16164G, C16266T, G5460A, T6680C, G9123A, A14587G, T16362C, and G709A) were associated with the occurrence of PTC. Here we report a comprehensive characterization of the mitochondrial genome and demonstrate its significance in pathogenesis and progression of PTC. This can help to clarify the molecular mechanisms underlying PTC and offer potential biomarkers or therapeutic targets for future clinical practice.

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Section: Discussionmentioning

confidence: 77%

A Comprehensive Characterization of Mitochondrial Genome in Papillary Thyroid Cancer

Wang

Ruan

et al. 2016

IJMS

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“…The common MELAS mutation m.3243A>G has been implicated in steroid-resistant focal segmental glomerulosclerosis [8], an Alport syndrome-like phenotype [9], maternally-inherited diabetes and deafness [10] and in a patient with renal cancer and nephrotic syndrome [11]. Patients with both isolated and syndromic renal disease have been found to have other, novel mtDNA mutations, such as a 7.3kB mtDNA deletion in a patient with renal Fanconi syndrome [12] and a frame-shift deletion of m.12425delA in a patient with Complex I deficiency, renal failure and myopathy [13]. Here, we add a new mtDNA mutation, m.586G>A, to the list of mitochondrial DNA mutations associated with renal disease and as a cause of chronic tubulointerstitial nephritis.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial tRNAPhe mutation as a cause of end-stage renal disease in childhood

et al. 2012

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Background We identified a mitochondrial tRNA mutation (m.586G>A) in a patient with renal failure and symptoms consistent with a mitochondrial cytopathy. This mutation was of unclear significance because there were neither consistent reports of linkage to specific disease phenotypes nor an existing analysis of effects upon mitochondrial function. Case-Diagnosis/Treatment A 16-month-old girl with failure-to-thrive, developmental regression, persistent lactic acidosis, hypotonia, GI dysmotility, adrenal insufficiency and hematologic abnormalities developed hypertension and renal impairment with chronic tubulointerstitial fibrosis, progressing to renal failure with need for peritoneal dialysis. Evaluation of her muscle and blood identified a mutation of the mitochondrial tRNA for phenylalanine, m.586G>A. Conclusions The m.586G>A mutation is pathogenic and is a cause of end-stage renal disease in childhood. The mutation interferes with the stability of tRNAPhe and affects the translation of mitochondrial proteins and the stability of the electron transport chain.

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“…Protein encoding mutations were included only if they were assigned as ‘probably’ or ‘definitely pathogenic’ using a validated scoring system designed in this laboratory [66]. Our database includes all such mutations previously assigned pathogenicity scores by Wong in 2007 [67], as well as 4 more recently published mutations which were shown to score in these categories [68]–[71]. We also included tRNA mutations proven to be pathogenic by a similar scoring system [72].…”

Section: Methodsmentioning

confidence: 99%

Comparison of Mitochondrial Mutation Spectra in Ageing Human Colonic Epithelium and Disease: Absence of Evidence for Purifying Selection in Somatic Mitochondrial DNA Point Mutations

et al. 2012

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Human ageing has been predicted to be caused by the accumulation of molecular damage in cells and tissues. Somatic mitochondrial DNA (mtDNA) mutations have been documented in a number of ageing tissues and have been shown to be associated with cellular mitochondrial dysfunction. It is unknown whether there are selective constraints, which have been shown to occur in the germline, on the occurrence and expansion of these mtDNA mutations within individual somatic cells. Here we compared the pattern and spectrum of mutations observed in ageing human colon to those observed in the general population (germline variants) and those associated with primary mtDNA disease. The pathogenicity of the protein encoding mutations was predicted using a computational programme, MutPred, and the scores obtained for the three groups compared. We show that the mutations associated with ageing are randomly distributed throughout the genome, are more frequently non-synonymous or frameshift mutations than the general population, and are significantly more pathogenic than population variants. Mutations associated with primary mtDNA disease were significantly more pathogenic than ageing or population mutations. These data provide little evidence for any selective constraints on the occurrence and expansion of mtDNA mutations in somatic cells of the human colon during human ageing in contrast to germline mutations seen in the general population.

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A novel mitochondrial MTND5 frameshift mutation causing isolated complex I deficiency, renal failure and myopathy

Cited by 31 publications

References 23 publications

A Comprehensive Characterization of Mitochondrial Genome in Papillary Thyroid Cancer

A Comprehensive Characterization of Mitochondrial Genome in Papillary Thyroid Cancer

Mitochondrial tRNAPhe mutation as a cause of end-stage renal disease in childhood

Comparison of Mitochondrial Mutation Spectra in Ageing Human Colonic Epithelium and Disease: Absence of Evidence for Purifying Selection in Somatic Mitochondrial DNA Point Mutations

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