<i>POLG</i>
            mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness

Mancuso, Michelangelo; Filosto, Massimiliano; Bellan, Marzio; Liguori, Rocco; Montagna, Pasquale; Baruzzi, Agostino; DiMauro, Salvatore; Carelli, Valério

doi:10.1212/wnl.62.2.316

Cited by 90 publications

(55 citation statements)

References 9 publications

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“…12 Conversely, in some pedigrees with hereditary chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease caused by multiple deletions of mtDNA, affected members have comorbid mood disorders (Table 1). 13,14,17,18,20,21 Deleted mtDNA was detected in the postmortem brains of bipolar patients, 22 and MRS features in bipolar disorder 23,24 resembled those seen in CPEO. 25,26 These findings prompted us to propose 'mitochondrial dysfunction hypothesis of bipolar disorder', 4 and other researchers have recently supported this hypothesis.…”

Section: Introductionmentioning

confidence: 91%

“…However, the relationship between the presence of mtDNA defects and the occurrence of specific clinical features of mitochondrial diseases still remains largely mysterious. In human patients carrying mutations in the POLG gene and consequent mtDNA defects, many associated phenotypes in addition to CPEO have been proposed; Parkinson's disease, 61 premature menopause, 61 ataxia, 62,63 sensorimotor polyneuropathy, 64 deafness, 17 diabetes mellitus, 64 and mood disorders. 13,17,63 Furthermore, mutant POLG knock-in mice showed cardiomyopathy, alopecia, osteoporosis, anaemia, reduced fertility, etc.…”

Section: Face Validitymentioning

confidence: 99%

“…In human patients carrying mutations in the POLG gene and consequent mtDNA defects, many associated phenotypes in addition to CPEO have been proposed; Parkinson's disease, 61 premature menopause, 61 ataxia, 62,63 sensorimotor polyneuropathy, 64 deafness, 17 diabetes mellitus, 64 and mood disorders. 13,17,63 Furthermore, mutant POLG knock-in mice showed cardiomyopathy, alopecia, osteoporosis, anaemia, reduced fertility, etc. 30,31 Thus, mtDNA defects and ensuing mitochondrial dysfunction enigmatically cause many kinds of phenotypes in various organs, suggesting that mutation in POLG is not a specific risk factor for mood disorder.…”

Section: Face Validitymentioning

confidence: 99%

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Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes

et al. 2006

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There is no established genetic model of bipolar disorder or major depression, which hampers research of these mood disorders. Although mood disorders are multifactorial diseases, they are sometimes manifested by one of pleiotropic effects of a single major gene defect. We focused on chronic progressive external ophthalmoplegia (CPEO), patients with which sometimes have comorbid mood disorders. Chronic progressive external ophthalmoplegia is a mitochondrial disease, which is accompanied by accumulation of mitochondrial DNA (mtDNA) deletions caused by mutations in nuclear-encoded genes such as POLG (mtDNA polymerase). We generated transgenic mice, in which mutant POLG was expressed in a neuron-specific manner. The mice showed forebrain-specific defects of mtDNA and had altered monoaminergic functions in the brain. The mutant mice exhibited characteristic behavioral phenotypes, a distorted day-night rhythm and a robust periodic activity pattern associated with estrous cycle. These abnormal behaviors resembling mood disorder were worsened by tricyclic antidepressant treatment and improved by lithium, a mood stabilizer. We also observed antidepressant-induced mania-like behavior and long-lasting irregularity of activity in some mutant animals. Our data suggest that accumulation of mtDNA defects in brain caused mood disorder-like mental symptoms with similar treatment responses to bipolar disorder. These findings are compatible with mitochondrial dysfunction hypothesis of bipolar disorder.

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Section: Introductionmentioning

confidence: 91%

Section: Face Validitymentioning

confidence: 99%

Section: Face Validitymentioning

confidence: 99%

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Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes

et al. 2006

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“…In support of this hypothesis, hearing loss is a common symptom in patients harboring inherited mtDNA mutations [56]. Several mutations in the Polg gene (mitochondrial DNA polymerase gamma) have been identified as a cause of human disorders such as Alpers syndrome and deafness [57,58]. Specific mtDNA point mutations also contribute to mitochondrial disorders in humans such as MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged red fibres), the symptoms of which include hearing loss [54,55,59].…”

Section: Delay Of Age-related Hearing Loss By Crmentioning

confidence: 95%

Effects of Caloric Restriction on Age-Related Hearing Loss in Rodents and Rhesus Monkeys

Someya¹,

Tanokura²,

Weindruch³

et al. 2010

CAS

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Age-related hearing loss (AHL), also known as presbycusis, is a universal feature of mammalian aging and is the most frequently occurring sensory disorder in the elderly population. AHL is characterized by a decline of auditory function and loss of hair cells and spiral ganglion neurons in the cochlea of the inner ear. It has been postulated that AHL occurs gradually as a result of the cumulative effect with aging of exposure to noise, diet, oxidative damage, and mitochondrial DNA mutations. However, the molecular mechanisms of AHL remain unclear and no preventative or therapeutic interventions have been developed. A growing body of evidence suggests increased oxidative damage with aging to macromolecules such as DNA, proteins, and lipids may play a causal role in aging and age-related diseases. Caloric restriction (CR) extends the lifespan of most mammalian species, delays the onset of multiple age-related diseases, and attenuates both the degree of oxidative damage and the associated decline in physiological function. Here, we review studies on CR's ability to prevent cochlear pathology and AHL in laboratory animals and discuss potential molecular mechanisms of CR's actions.

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“…The H932Y mutation is found as a compound with T251I/P587L and with G1051R (12,13). A preliminary pre-steady state kinetic study of nucleotide incorporation on H932Y mutation of human pol ␥ has quantified the effect of the mutation of the kinetics of correct nucleotide incorporation (14), but the role of His-932 in nucleotide selectivity has not been determined.…”

mentioning

confidence: 99%

Role of Histidine 932 of the Human Mitochondrial DNA Polymerase in Nucleotide Discrimination and Inherited Disease

Batabyal

McKenzie

Johnson

2010

Journal of Biological Chemistry

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The human mitochondrial DNA polymerase (pol ␥) is nuclearly encoded and is solely responsible for the replication and repair of the mitochondrial genome. The progressive accumulation of mutations within the mitochondrial genome is thought to be related to aging, and mutations in the pol ␥ gene are responsible for numerous heritable disorders including progressive external opthalmoplegia, Alpers syndrome, and parkinsonism. Here we investigate the kinetic effect of H932Y, a mutation associated with opthalmoplegia. Mutations H932Y and H932A reduce the specificity constant governing correct nucleotide incorporation 150-and 70-fold, respectively, without significantly affecting fidelity of incorporation or the maximum rate of incorporation. However, this leads to only a 2-fold reduction in rate of incorporation at a physiological nucleotide concentration (ϳ100 M). Surprisingly, incorporation of T:T or C:T mismatches catalyzed by either H932Y or H932A mutants was followed by slow pyrophosphate release (or fast pyrophosphate rebinding). Also, H932Y readily catalyzed incorporation of multiple mismatches, which may have a profound physiological impact over time. His-932 is thought to contact the ␤-phosphate of the incoming nucleotide, so it is perhaps surprising that H932Y appears to slow rather than accelerate pyrophosphate release. Mutations in DNA polymerase ␥ (pol ␥)2 have been linked to several mitochondrial disorders that include progressive external opthalmoplegia (PEO), Alpers syndrome, parkinsonism, male infertility, and SANDO (sensory ataxic neuropathy, dysarthria, and opthalmoparesis) among others (1). The majority of the mutations in pol ␥ are associated with PEO, a mitochondrial disorder associated with accumulation of mitochondrial DNA deletions and mutations. The main clinical manifestation of PEO is progressive weakness of the external eye muscles and is often accompanied by dysphagia and variable weakness of the limb and neck muscles. Neurological symptoms could include depression or avoidant personality (2). Greater than 60 pathogenic mutations in the pol ␥A gene are associated with PEO, including about 14 dominant mutations, 36 recessive mutations, and other mutations of sporadic or unknown origin (1).Recently the crystal structure of the human pol ␥ was solved by Lee et al. (3) and has provided an insight into understanding how processivity is achieved by the holoenzyme. The structure provides a framework to examine the physiological basis of heritable mutations in pol ␥. Pol ␥ is a heterotrimer in which one molecule of the catalytic subunit (pol ␥A) binds to a dimeric pol ␥B. Similar to most DNA polymerases, the structure of pol ␥A resembles a human right hand with "palm," "fingers," and "thumb" domains (4, 5). The palm domain is responsible for the catalysis of the phosphoryl transfer reaction, and the fingers domain is proposed to be involved in binding of the templating base and the incoming nucleotide and governs the fidelity of the DNA polymerase. The structures of the fingers domain differ bet...

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POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness

Cited by 90 publications

References 9 publications

Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes

Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes

Effects of Caloric Restriction on Age-Related Hearing Loss in Rodents and Rhesus Monkeys

Role of Histidine 932 of the Human Mitochondrial DNA Polymerase in Nucleotide Discrimination and Inherited Disease

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