Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia

Goethem, Gert Van; Martin, J.J.; Dermaut, Bart; Löfgren, A.; Wibail, Alain; Ververken, D; Tack, Peter I.; Dehaene, I.; Zandijcke, M. Van; Moonen, M; Ceuterick, C.; Jonghe, Peter De; Broeckhoven, Christine Van

doi:10.1016/s0960-8966(02)00216-x

Cited by 220 publications

(153 citation statements)

References 32 publications

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“…This mutation has already been reported in arPEO Belgian families presenting with features of the SANDO syndrome, but only in combination with the c.1399G4A substitution (A467T). 5 We describe, for the first time, the L304R mutation in a homozygous state in a patient presenting with a SANDO phenotype. The A467T mutation was found in a heterozygous state in patient C, in combination with a new c.1139G4A substitution.…”

Section: Resultsmentioning

confidence: 93%

Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay

et al. 2006

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ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome. A total of seven different mutations were identified in six of 15 patients (40%). Six different recessive mutations were found in POLG, one in TWINKLE while no mutation was identified in ANT1. Among the POLG mutations, three are novel and include two missense and one frameshift changes. Seventeen neutral changes and polymorphisms were also identified, including four novel neutral polymorphisms. Overall, this study illustrates the variability of phenotypes associated with mtDNA stability defects, increases the mutational spectrum of POLG variants and provides an efficient and reliable detection protocol for ANT1, TWINKLE and POLG mutational screening.

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Section: Resultsmentioning

confidence: 93%

Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay

et al. 2006

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“…Available functional evidence on the consequences of A467T and W748S mutations for POLG, however, does not support selective advantage for them, since the mutant enzymes are catalytically defective, 17,28 and would lead to mtDNA depletion and/or increased mutagenesis. Furthermore, the frequency of the A467T mutation in Australia (Thorburn et al, manuscript in preparation) seems to parallel the observed frequencies in European countries (0.6% in Belgium and 1% in Norway 13,15 ), reflecting the European origin of the Australians. The occurrence of A467T mutation, therefore, seems to support random segregation over many centuries.…”

Section: Discussionmentioning

confidence: 74%

“…13,15 In our previous haplotype analysis of the European A467T disease chromosomes, a long common haplotype was seen in the British and Belgian patients and remnants of this haplotype were also seen in Norwegian patients, raising the possibility of a common founder also for the A467T mutation. 12 Here, we studied the haplotypes of patients with W748S and A467T mutations from Australia, New Zealand, and the United States to determine whether these mutations would originate from European founders or rather result from recurrent mutation events.…”

Section: Introductionmentioning

confidence: 91%

Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

et al. 2007

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We reported previously that the DNA polymerase c (POLG) W748S mutation, a common cause of mitochondrial recessive ataxia syndrome (MIRAS), has a common ancient founder for all the disease chromosomes in Finland, Norway, United Kingdom, and Belgium. Here, we present results showing that the same ancestral chromosome underlies MIRAS and Alpers syndrome in Australia and New Zealand. Furthermore, we show that a second common POLG mutation, A467T, also shows common European ancestry: patients from Australia, New Zealand, and the United States share a common haplotype with the previously reported European patients. These data of ancestral haplotypes indicate that the POLG locus is quite stable and that the recessive W748S and A467T mutations, and probably also G848S, have occurred once in history. They have effectively spread to populations of European descent with carrier frequencies up to 1% in several populations. Our data predict that these mutations are common causes of ataxia and Alpers disease in the Western world.

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“…9 The fact that axonal predominantly sensory peripheral neuropathy is common in recessive PEO patients with POLG mutations, 6 prompted us to analyze POLG. Sequencing of all coding POLG exons using flanking intronic primers 4 in the proband (II.4) revealed the presence of three single-base changes.…”

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confidence: 99%

Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy

et al. 2003

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Autosomal recessive progressive external ophthalmoplegia (PEO) is one clinical disorder associated with multiple mitochondrial DNA deletions and can be caused by missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is another autosomal recessive disorder associated with PEO and multiple deletions of mitochondrial DNA in skeletal muscle. In several patients this disorder is caused by loss of function mutations in the gene encoding thymidine phosphorylase (TP). We report a recessive family with features of MNGIE but no leukoencephalopathy in which two patients carry three missense mutations in POLG, of which two are novel mutations (N846S and P587L). The third mutation was previously reported as a recessive POLG mutation (T251I). This finding indicates the need for POLG sequencing in patients with features of MNGIE without TP mutations.

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Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia

Cited by 220 publications

References 32 publications

Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay

Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay

Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy

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