A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma

Siibak, Triinu; Clemente, Paula; Bratić, Ana; Bruhn, Helene; Kauppila, Timo E.S.; Macao, Bertil; Schober, F.; Lesko, Nicole; Wibom, Rolf; Naess, K; Nennesmo, Inger; Wedell, Anna; Peter, Bradley; Freyer, Christoph; Falkenberg, Maria; Wredenberg, Anna

doi:10.1093/hmg/ddx146

Cited by 14 publications

(17 citation statements)

References 44 publications

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“…1 D , SI Appendix , Fig. S2 A and B , and Dataset S1 ), which is in line with our recent findings showing that two dominant negative DmPOLγA alleles (Y873C and Y873H) do not limit the lifespan of fruit flies ( 37 ). Surprisingly, an increase in the somatic mtDNA mutation load did not have any effect on the lifespan in exonuclease-deficient (+/D263A F 0 ) flies ( Fig.…”

Section: Resultssupporting

confidence: 90%

Mutations of mitochondrial DNA are not major contributors to aging of fruit flies

Kauppila

Bratić

Jensen

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceMutations of mtDNA accumulate in aging humans and other mammals to cause mitochondrial dysfunction in a subset of cells in various tissues. Furthermore, experimental induction of mtDNA mutations causes a premature aging syndrome in the mouse. To study if mitochondrial dysfunction is universally involved in shortening life span in metazoans, we generated a series of fruit fly lines with varying levels of mtDNA mutations. Unexpectedly, we report that fruit flies are remarkably tolerant to mtDNA mutations, as exemplified by their lack of effect on physiology and lifespan. Only an artificially induced, very drastic increase of the mtDNA mutation load will lead to reduced lifespan, showing that mtDNA mutations are unlikely to limit lifespan in natural fruit fly populations.

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Section: Resultssupporting

confidence: 90%

Mutations of mitochondrial DNA are not major contributors to aging of fruit flies

Kauppila

Bratić

Jensen

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to c.1880G>A/p. R627Q, c.2591A>G/p.N864S, c.2864A>G/p.Y955C, and c.3287G>A/p.R1096H, which have been previously reported as pathogenic mutations (Horvath et al, 2006;Luoma et al, 2005;Siibak et al, 2017;Van Goethem et al, 2003), nine novel mutations were found, namely one frameshift mutation (c.3002delG/p.G1001fs) and eight missense mutations (c.668G>C/p.W223S, c.703T>C/p. W235R, c.914G>A/p.S305N, c.923A>G/p.Q308R, c.924G>T/p.Q308H, c.1790G>A/p.R597Q, c.1832C>T/p.…”

Section: Polg Genementioning

confidence: 89%

Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple mtDNA deletions

Hou

Zhao

Xie

et al. 2022

Molec Gen & Gen Med

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Objectives This study aimed to investigate the clinical and genetic spectrum in Chinese patients with multiple mtDNA deletions presenting with autosomal‐inherited mitochondrial progressive external ophthalmoplegia (PEO). Methods Long‐range polymerase chain reaction and massively parallel sequencing of the mitochondrial genome were performed to detect deletions in muscle mtDNA of 274 unrelated families. Then, targeted next generation sequencing was used to detect nuclear gene variations in patients with multiple mtDNA deletions. Results A total of 40 Chinese PEO patients (10 males and 30 females) from 20 families were found to have multiple mtDNA deletions in this study, and the median age at onset was 35 (1–70) years. PEO and positive family history were the two prominent features of these patients, and ataxia, neuropathy, and hypogonadism were also present as onset symptoms in some patients. Fifteen of 20 probands with multiple mtDNA deletions were identified to carry nuclear gene variants; eight (40.0%) probands had variants within POLG , two (10.0%) within TWNK , two (10.0%) within RRM2B , two (10.0%) within TK2 , and one (5.0%) within POLG2 . A total of 24 variants were found in these five nuclear genes, of which 19 were novel. The causal nuclear genetic factors in five pedigrees remain undetermined. Conclusions The POLG gene is the most common disease‐causing gene in this group of PEO patients with multiple mtDNA deletions. While inherited PEO is the most prominent symptoms in these patients, genotypic and phenotypic heterogeneity still exist, for example in onset age, initial symptoms, and accompanying manifestations.

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“…Mutations in this gene were first identified via a screen for altered larval responses to light (resulting in the gene being named 'tamas' -Sanskrit for 'dark inertia')indeed, these were the first reported mutations in any PolG gene [107]. Mutants die during late larval stages, exhibiting impaired mtDNA replication and decreased mtDNA content [107][108][109]. Ubiquitous RNAi-mediated knock-down of PolG1 depletes mtDNA, decreases mitochondrial respiratory activity and results in lethality, while neuronal-specific knock-down causes progressive behavioral deficits [110,111].…”

Section: Mitochondrial Polymerasementioning

confidence: 99%

“…Mutations in human POLG and POLG2 are associated with several diseases including mtDNA depletion syndromes, such as Alpers syndrome, and mtDNA deletion disorders, such as progressive external ophthalmoplegia [121]. Significantly, several studies in the last decade have manipulated the orthologous D. melanogaster genes to provide important insights into the etiology of, and possible therapies for, these diseases [108][109][110][111][112][113]122]. For example, two studies generated flies expressing exonuclease-or polymerase-deficient versions of PolG1 in order to investigate how defects in these two different activities of the enzyme may contribute to pathophysiology [112,113].…”

Section: Mitochondrial Polymerasementioning

confidence: 99%

“…Two other investigations studied the effects of mutations or knock-down of D. melanogaster PolG1 or PolG2 specifically in the nervous system to probe how mitochondrial dysfunction may lead to neuropathies and neurodegenerative disorders in humans [ 108 , 110 ]. As a final example, Siibak et al engineered the endogenous PolG1 gene in flies to have mutations equivalent to those found in patients to probe their molecular and physiological consequences, finding that both mutations cause mtDNA depletion [ 109 ].…”

Section: Research On D Melanogaster Dna Polymerasesmentioning

confidence: 99%

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The DNA polymerases of Drosophila melanogaster

Marygold

Attrill

Speretta

et al. 2020

Fly

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DNA synthesis during replication or repair is a fundamental cellular process that is catalyzed by a set of evolutionary conserved polymerases. Despite a large body of research, the DNA polymerases of Drosophila melanogaster have not yet been systematically reviewed, leading to inconsistencies in their nomenclature, shortcomings in their functional (Gene Ontology, GO) annotations and an under-appreciation of the extent of their characterization. Here, we describe the complete set of DNA polymerases in D. melanogaster, applying nomenclature already in widespread use in other species, and improving their functional annotation. A total of 19 genes encode the proteins comprising three replicative polymerases (alpha-primase, delta, epsilon), five translesion/repair polymerases (zeta, eta, iota, Rev1, theta) and the mitochondrial polymerase (gamma). We also provide an overview of the biochemical and genetic characterization of these factors in D. melanogaster. This work, together with the incorporation of the improved nomenclature and GO annotation into key biological databases, including FlyBase and UniProtKB, will greatly facilitate access to information about these important proteins.

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A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma

Cited by 14 publications

References 44 publications

Mutations of mitochondrial DNA are not major contributors to aging of fruit flies

Mutations of mitochondrial DNA are not major contributors to aging of fruit flies

Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple mtDNA deletions

The DNA polymerases of Drosophila melanogaster

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