Whole exome sequencing identifies a homozygous POLG2 missense variant in an adult patient presenting with optic atrophy, movement disorders, premature ovarian failure and mitochondrial DNA depletion

Došekova, Petra; Dubiel, A; Karlowicz, Anna; Ziętkiewicz, Szymon; Rydzanicz, Małgorzata; Habalová, Viera; Pienkowski, Victor Murcia; Skirkova, Miriam; Han, Vladimir; Mosejova, Alexandra; Gdovinová, Zuzana; Kaliszewska, Magdalena; Tońska, Katarzyna; Szymanski, Michal R.; Škorvánek, Matej; Płoski, Rafał

doi:10.1016/j.ejmg.2019.103821

Cited by 7 publications

(2 citation statements)

References 21 publications

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“…In comparison to the POLγA-related neurological diseases, a relatively less neuronal pathology is linked to the mutation in POLγB. However, one research reported that one patient with childhood-onset and progressive neuro-ophthalmic manifestation with optic atrophy, mixed polyneuropathy, spinal and cerebellar ataxia, and generalized chorea, is caused by a homozygous missense mutation in POLG2 p.D433Y, which is associated with mtDNA depletion (Dosekova et al, 2020 ).…”

Section: Dysregulation Of Mitochondrial Genome Maintenancementioning

confidence: 99%

Mitochondrial protein dysfunction in pathogenesis of neurological diseases

Wang

Zhou

et al. 2022

Front. Mol. Neurosci.

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Mitochondria are essential organelles for neuronal function and cell survival. Besides the well-known bioenergetics, additional mitochondrial roles in calcium signaling, lipid biogenesis, regulation of reactive oxygen species, and apoptosis are pivotal in diverse cellular processes. The mitochondrial proteome encompasses about 1,500 proteins encoded by both the nuclear DNA and the maternally inherited mitochondrial DNA. Mutations in the nuclear or mitochondrial genome, or combinations of both, can result in mitochondrial protein deficiencies and mitochondrial malfunction. Therefore, mitochondrial quality control by proteins involved in various surveillance mechanisms is critical for neuronal integrity and viability. Abnormal proteins involved in mitochondrial bioenergetics, dynamics, mitophagy, import machinery, ion channels, and mitochondrial DNA maintenance have been linked to the pathogenesis of a number of neurological diseases. The goal of this review is to give an overview of these pathways and to summarize the interconnections between mitochondrial protein dysfunction and neurological diseases.

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Section: Dysregulation Of Mitochondrial Genome Maintenancementioning

confidence: 99%

Mitochondrial protein dysfunction in pathogenesis of neurological diseases

Wang

Zhou

et al. 2022

Front. Mol. Neurosci.

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“…Homozygous Polγ knockout mice are inviable in utero due to an early developmental arrest (Hance et al, 2005 ). Mutations in Polγ are reported to be associated with neurodegenerative diseases in which skeletal muscle and nervous tissues are most frequently affected, e.g., progressive external ophthalmoplegia and Alpers' syndrome (a progressive, neurodevelopmental, mitochondrial DNA depletion syndrome) (Hedberg-Oldfors et al, 2020 ) and case of progressive neuro-ophthalmic manifestation with optic atrophy, mixed polyneuropathy, spinal and cerebellar ataxia, and generalized chorea (Dosekova et al, 2020 ) ( Figure 2 ). There is also evidence that mutations or alterations in expression in Polγ are associated with AD (Wallace, 2005 ) and PD (Kraytsberg et al, 2006 ).…”

Section: Dna Polymerases That Are Active In Neurons In Response To Dn...mentioning

confidence: 99%

Polymerases and DNA Repair in Neurons: Implications in Neuronal Survival and Neurodegenerative Diseases

Cao

Liu

et al. 2022

Front. Cell. Neurosci.

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Most of the neurodegenerative diseases and aging are associated with reactive oxygen species (ROS) or other intracellular damaging agents that challenge the genome integrity of the neurons. As most of the mature neurons stay in G0/G1 phase, replication-uncoupled DNA repair pathways including BER, NER, SSBR, and NHEJ, are pivotal, efficient, and economic mechanisms to maintain genomic stability without reactivating cell cycle. In these progresses, polymerases are prominent, not only because they are responsible for both sensing and repairing damages, but also for their more diversified roles depending on the cell cycle phase and damage types. In this review, we summarized recent knowledge on the structural and biochemical properties of distinct polymerases, including DNA and RNA polymerases, which are known to be expressed and active in nervous system; the biological relevance of these polymerases and their interactors with neuronal degeneration would be most graphically illustrated by the neurological abnormalities observed in patients with hereditary diseases associated with defects in DNA repair; furthermore, the vicious cycle of the trinucleotide repeat (TNR) and impaired DNA repair pathway is also discussed. Unraveling the mechanisms and contextual basis of the role of the polymerases in DNA damage response and repair will promote our understanding about how long-lived postmitotic cells cope with DNA lesions, and why disrupted DNA repair contributes to disease origin, despite the diversity of mutations in genes. This knowledge may lead to new insight into the development of targeted intervention for neurodegenerative diseases.

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POLG2-Linked Mitochondrial Disease: Functional Insights from New Mutation Carriers and Review of the Literature

et al. 2023

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Different pathogenic variants in the DNA polymerase-gamma2 (POLG2) gene cause a rare, clinically heterogeneous mitochondrial disease. We detected a novel POLG2 variant (c.1270 T > C, p.Ser424Pro) in a family with adult-onset cerebellar ataxia and progressive ophthalmoplegia. We demonstrated altered mitochondrial integrity in patients’ fibroblast cultures but no changes of the mitochondrial DNA were found when compared to controls. We consider this novel, segregating POLG2 variant as disease-causing in this family. Moreover, we systematically screened the literature for POLG2-linked phenotypes and re-evaluated all mutations published to date for pathogenicity according to current knowledge. Thereby, we identified twelve published, likely disease-causing variants in 19 patients only. The core features included progressive ophthalmoplegia and cerebellar ataxia; parkinsonism, neuropathy, cognitive decline, and seizures were also repeatedly found in adult-onset heterozygous POLG2-related disease. A severe phenotype relates to biallelic pathogenic variants in POLG2, i.e., newborn-onset liver failure, referred to as mitochondrial depletion syndrome. Our work underlines the broad clinical spectrum of POLG2-related disease and highlights the importance of functional characterization of variants of uncertain significance to enable meaningful genetic counseling.

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Whole exome sequencing identifies a homozygous POLG2 missense variant in an adult patient presenting with optic atrophy, movement disorders, premature ovarian failure and mitochondrial DNA depletion

Cited by 7 publications

References 21 publications

Mitochondrial protein dysfunction in pathogenesis of neurological diseases

Mitochondrial protein dysfunction in pathogenesis of neurological diseases

Polymerases and DNA Repair in Neurons: Implications in Neuronal Survival and Neurodegenerative Diseases

POLG2-Linked Mitochondrial Disease: Functional Insights from New Mutation Carriers and Review of the Literature

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