The in cis T251I and P587L POLG1 base changes: Description of a new family and literature review

Scuderi, Carmela; Borgione, Eugenia; Castello, Filippa; Giudice, Mariangela Lo; Paola, Sandro Santa; Giambirtone, Mariaconcetta; Blasi, Francesco Domenico Di; Elia, Maurizio; Amato, Carmelo; Città, Santina; Gagliano, Catalda; Barbarino, G. C.; Vitello, Girolamo Aurelio; Musumeci, S

doi:10.1016/j.nmd.2015.01.004

Cited by 20 publications

(15 citation statements)

References 34 publications

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“…However, the onset age and progression of POLG-related disease in patients with the same POLG mutations can span several decades, making predictions difficult. For example, a review of patients with T251I-P587L in trans with G848S showed that the presentation of disease spans >70 years 73 , and another review revealed that disease related to homozygosity for A467T spans at least four decades of life 65,68 . This enigma of presentation suggests that other factors modify the POLG disease phenotype, including genetic modifiers (nuclear DNA or mtDNA), immune dysfunction, and environmental effects such as viral infection and mitochondrial toxins 74,75 .…”

Section: [H1] Pathophysiologymentioning

confidence: 99%

POLG-related disorders and their neurological manifestations

2018

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The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying POLG mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers-Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and Autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions.

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Section: [H1] Pathophysiologymentioning

confidence: 99%

POLG-related disorders and their neurological manifestations

2018

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“…They are compound heterozygotes and often occur with common Pol γ mutations, such as A467T (Van Goethem et al, 2003a), W748S (Van Goethem et al, 2004), R309L (Lamantea et al, 2002), G848S (Lamantea et al, 2002), R627W (Van Goethem et al, 2003a), N846S (Van Goethem et al, 2003c) or T251I in cis with P587L (Lamantea et al, 2002; Scuderi et al, 2015), to name a few. Patients with arPEO have the same clinical features as with adPEO, but with greater variation in symptoms and time of onset.…”

Section: Age-related Mitochondrial Diseases Associated With Defectmentioning

confidence: 99%

Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases

DeBalsi

Hoff

Copeland

2017

Ageing Research Reviews

149

124

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As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined.

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“…Scuderi et al (19) recently compiled a comprehensive list of clinical phenotypes and genetic characteristics of the approximately 50 cases of T251I ϩ P587L mentioned in the literature. The main clinical presentation is PEO, with or without ptosis, and secondary clinical features include ataxia, myopathy, epilepsy, neuropathy, and hepatic diseases.…”

mentioning

confidence: 99%

Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations

DeBalsi

Longley

Hoff

et al. 2017

Journal of Biological Chemistry

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Human mitochondrial DNA (mtDNA) polymerase γ (Pol γ) is the only polymerase known to replicate the mitochondrial genome. The Pol γ holoenzyme consists of the p140 catalytic subunit (POLG) and the p55 homodimeric accessory subunit (POLG2), which enhances binding of Pol γ to DNA and promotes processivity of the holoenzyme. Mutations within impede maintenance of mtDNA and cause mitochondrial diseases. Two common mutations usually found in patients primarily with progressive external ophthalmoplegia generate T251I and P587L amino acid substitutions. To determine whether T251I or P587L is the primary pathogenic allele or whether both substitutions are required to cause disease, we overproduced and purified WT, T251I, P587L, and T251I + P587L double variant forms of recombinant Pol γ. Biochemical characterization of these variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromised DNA processivity, even in the presence of the p55 accessory subunit. However, physical association with p55 was unperturbed, suggesting intersubunit affinities similar to WT. Notably, although the single mutants were similarly impaired, a dramatic synergistic effect was found for the double mutant across all parameters. In conclusion, our analyses suggest that individually both T251I and P587L substitutions functionally impair Pol γ, with greater pathogenicity predicted for the single P587L variant. Combining T251I and P587L induces extreme thermal lability and leads to synergistic nucleotide and DNA binding defects, which severely impair catalytic activity and correlate with presentation of disease in patients.

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The in cis T251I and P587L POLG1 base changes: Description of a new family and literature review

Cited by 20 publications

References 34 publications

POLG-related disorders and their neurological manifestations

POLG-related disorders and their neurological manifestations

Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases

Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations

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