Patient homozygous for a recessive
            <i>POLG</i>
            mutation presents with features of MERRF

Goethem, Gert Van; Mercelis, R.; Löfgren, A.; Seneca, Sara; Ceuterick, C.; Martin, Jean‐Jacques; Broeckhoven, Christine Van

doi:10.1212/01.wnl.0000098997.23471.65

Cited by 72 publications

(60 citation statements)

References 9 publications

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“…In addition, a homozygous A467T patient presented with a myoclonic epilepsy with ragged red fibers (MERRF)-like syndrome at age 15 exhibited low levels of mtDNA deletions in the muscle (33). In contrast, those who are heterozygous for the A467T mutation (WT/A467T) do not show any symptoms of disease (5)(6)(7)(8)(9)(10)(11)(12)33), 2 although one recent study reported a mild dominant manifestation of late-onset ptosis in a patient heterozygous for the A467T mutation (31). In an extreme example of this gene dose effect, we have recently shown that mono-allelic expression of an A467T allele was linked to a case of Alpers syndrome with early onset at 18 months followed by death at 42 months (35).…”

Section: Discussionmentioning

confidence: 99%

The Common A467T Mutation in the Human Mitochondrial DNA Polymerase (POLG) Compromises Catalytic Efficiency and Interaction with the Accessory Subunit

Chan

Longley

Copeland

2005

Journal of Biological Chemistry

119

148

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Among the nearly 50 disease mutations in the gene for the catalytic subunit of human DNA polymerase ␥, POLG, the A467T substitution is the most common and has been found in 0.6% of the Belgian population. The A467T mutation is associated with a wide range of mitochondrial disorders, including Alpers syndrome, juvenile spinocerebellar ataxia-epilepsy syndrome, and progressive external ophthalmoplegia, each with vastly different clinical presentations, tissue specificities, and ages of onset. The A467T mutant enzyme possesses only 4% of wild-type DNA polymerase activity, and the catalytic defect is manifest primarily through a 6-fold reduction in k cat with minimal effect on exonuclease function. Human DNA polymerase ␥ (pol ␥) requires association of a 55-kDa accessory subunit for enhanced DNA binding and highly processive DNA synthesis. However, the A467T mutant enzyme failed to interact with and was not stimulated by the accessory subunit, as judged by processivity, heat inactivation, and N-ethylmaleimide protection assays in vitro. Thermolysin digestion and immunoprecipitation experiments further indicate weak association of the subunits for A467T pol ␥. This is the first example of a mutation in POLG that disrupts physical association of the pol ␥ subunits. We propose that reduced polymerase activity and loss of accessory subunit interaction are responsible for the depletion and deletion of mitochondrial DNA observed in patients with this POLG mutation.

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Section: Discussionmentioning

confidence: 99%

The Common A467T Mutation in the Human Mitochondrial DNA Polymerase (POLG) Compromises Catalytic Efficiency and Interaction with the Accessory Subunit

Chan

Longley

Copeland

2005

Journal of Biological Chemistry

119

148

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“…First, the lack of ophthalmoplegia and prominence of myopathy sets these patients apart from other POLG syndromes. Second, histochemical assays of the muscle reveal the absence of ragged-red fibers distinguishing this syndrome from myoclonus epilepsy with raggedred fibers (Van Goethem et al 2003b). …”

Section: Myoclonic Epilepsy Myopathy Sensory Ataxia (Memsa)mentioning

confidence: 99%

Clinical and Molecular Features of POLG-Related Mitochondrial Disease

Stumpf

Saneto

Copeland

2013

Cold Spring Harbor Perspectives in Biology

113

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“…Other neurologic symptoms include migraine with visual auras, cortical blindness, hypotonia, ataxia, extrapyramidal movements, peripheral neuropathy, and progressive spastic paraparesis [63]. Non-neurologic manifestations include renal tubular acidosis, hearing loss, cyclic vomiting, and pancreatitis [64].…”

Section: Ahsmentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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Primary mitochondrial disorders are clinically and genetically heterogeneous, caused by an alteration(s) in either mitochondrial DNA or nuclear DNA, and affect the respiratory chain's ability to undergo oxidative phosphorylation, leading to decreased production of adenosine triphosphophate and subsequent energy failure. These disorders may present at any age, but children tend to have an acute onset of disease compared with subacute or slowly progressive presentation in adults. Varying organ involvement also contributes to the phenotypic spectrum seen in these disorders. The childhood presentation of primary mitochondrial disease is mainly due to nuclear DNA mutations, with mitochondrial DNA mutations being less frequent in childhood and more prominent in adulthood disease. The clinician should be aware of the pediatric presentation of mitochondrial disease and have an understanding of the myriad of nuclear genes responsible for these disorders. The nuclear genes can be best understood by utilizing a classification system of location and function within the mitochondria.

show abstract

Patient homozygous for a recessive POLG mutation presents with features of MERRF

Cited by 72 publications

References 9 publications

The Common A467T Mutation in the Human Mitochondrial DNA Polymerase (POLG) Compromises Catalytic Efficiency and Interaction with the Accessory Subunit

The Common A467T Mutation in the Human Mitochondrial DNA Polymerase (POLG) Compromises Catalytic Efficiency and Interaction with the Accessory Subunit

Clinical and Molecular Features of POLG-Related Mitochondrial Disease

Mitochondrial Disease in Childhood: Nuclear Encoded

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