The A467T and W748S POLG substitutions are a rare cause of adult-onset ataxia in Europe
1Mitochondrial Research Group, 2Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK, 3Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Neurological Institute and 4Division of Biochemistry and Genetics, National Neurological Institute, Milan, Italy
Correspondence to: Prof. Patrick F. Chinnery, M4014, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK E-mail: p.f.chinnery{at}ncl.ac.uk
Received October 16, 2006. Revised January 9, 2007. Accepted January 11, 2007.
In a recent edition of Brain, Tzoulis and colleagues (Tzoulis et al., 2006
) described the presentation and natural history of neurological disease due to the c.1399G 
A/A467T and c.2243G C/W748S mutations in POLG. POLG codes for mitochondrial DNA (mtDNA) polymerase (pol 
), the only polymerase present within mitochondria (Kaguni, 2004). Pathogenic POLG mutations were first described in autosomal dominant and recessive progressive external ophthalmoplegia (PEO) (Van Goethem et al., 2001), and more recently in recessive late-onset ataxia with peripheral neuropathy (Van Goethem et al., 2003; Winterthun et al., 2005), and the Alpers–Huttenlocher syndrome (Naviaux and Nguyen, 2004; Davidzon et al., 2005; Ferrari et al., 2005). Hakonen et al. (2005) recently reported the high carrier frequency of the W748S POLG substitution in control subjects in Finland (1 : 125 controls), explaining the high prevalence of mitochondrial recessive ataxia syndrome (MIRAS) in Scandinavia. Haplotype analysis revealed a common POLG haplotype in Finnish, Norwegian, Belgian and British subjects carrying W748S, raising the possibility that the same substitution is a common cause of late-onset ataxia throughout Europe (Hakonen et al., 2005). In Norway, c.1491G C/Q497H and A467T have also been described in adults with ataxia (Winterthun et al., 2005), often without ophthalmoplegia in the early stages. A467T is common in Europeans with an allele frequency of between 0.17 and 0.69% (Horvath et al., 2006), raising the possibility that this substitution is also a common cause of ataxia in other populations.
Late-onset ataxia affects 
1 in 10 000 adults, and despite major advances in our understanding of the clinical syndromes and molecular aetiology, it is not possible to reach a specific diagnosis in a large proportion of patients (Pulst, 2003). To determine whether the A467T and W748S substitutions are a common cause of ataxia outside Scandinavia, we studied two independent cohorts of patients with adult-onset ataxia who did not have a specific diagnosis. In one cohort we also looked for Q497H.
UK cohort: One hundred and ninety-two patients from UK with adult-onset ataxia who did not have a specific diagnosis. This cohort has been studied exhaustively for inflammatory, metabolic, neoplastic and sporadic degenerative causes of ataxia, and also tested for SCA 1, 2, 3, 6, 7, 10, 12, 17, dentatorubropalidoluysian atrophy (DRPLA) and Friedreich's ataxia (FA). Italian cohort: Ninety-six consecutive cases of ataxia, nine of whom had epilepsy. Molecular testing for DRPLA and the SCA genes most frequently found in Italians (i.e. SCA1 and SCA2, and in some cases also FA, SCA3, 6, 7, 17, sought in accordance with the clinical phenotype) was negative. Seventy-two individuals suffered a sporadic disease, dominant transmission was present in 16 subjects and ascertained recessive transmission in 8.
For the UK cohort, exons 8 and 13 of POLG were directly sequenced to determine which patients harboured Q479H and W748S (Beckman Coulter CEQ8000) (Horvath et al., 2006), and A467T was detected by PCR amplification of exon 7 followed by restriction digestion. The frequency of the substitutions in ataxic patients was compared to control subjects from the same geographic region [previously published data (Horvath et al., 2006)]. The Italian samples were screened using denaturing high performance chromatography as described (Lamantea et al., 2002).
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Results and Discussion |
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Two of the 192 UK patients with ataxia were heterozygous for c.2254C
T which is not predicted to alter the amino-acid sequence. A different patient with ataxia was heterozygous for A467T. The remaining exons of POLG were sequenced in this subject, identifying a second heterozygous substitution, c.3248G A/E1143G. Her clinically unaffected mother was heterozygous for E1143G, and her clinically unaffected father was heterozygous for A467T. A467T was detected in 3 of 432 control chromosomes (0.69%, exact 95% CI = 0.14–2.02), and E1143G was detected in 4 of 192 control chromosomes (2.08%, exact 95% CI = 0.57–5.25). Individually the frequency of A467T and E1143G in the UK ataxia cohort was not significantly different from controls (Fisher's exact P for A467T = 1.0 and E1143G = 0.37). However, the probability of observing both substitutions by chance in the same individual in the general population was P = 0.00014. Therefore, the chance of finding both A467T and E1143G in the same subject, in conjunction with a rare disease phenotype consistent with a recessive disorder due to POLG mutations, strongly suggests that the alleles are aetiologically linked to the ataxia in this individual. This could be due to a direct effect of each substitution on the polymerase, or because E1143G is tightly linked to another pathogenic mutation (such as a non-coding region substitution or an exon rearrangement). None of the UK patients harboured Q479H or W748S (including the patient with E1143G). Neither A467T nor W748S were detected in the Italian subjects.
Ataxia has been described in patients with mutations in other exons of POLG, and we cannot exclude the possibility that other substitutions are responsible for the ataxia in our cohort. However, although A467T and W748S are a common cause of ataxia in Scandinavia, they are rare in the United Kingdom and Italy. It is therefore likely that the high prevalence of MIRAS in Finland and Norway is due to a founder effect as for other recessive disorders that are over-represented in these countries. Our observations add to the growing body of evidence which implicates E1143G in the pathophysiology of disease (Hisama et al., 2005; Horvath et al., 2006). E1143G alters a conserved glutamic acid to glycine, and from first principles is likely to alter protein function. It is therefore remarkable that the substitution is present in up to 4% control subjects, possibly contributing to the pathophysiology of a broad range of different phenotypes.
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Acknowledgements |
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This study was funded by Ataxia (UK). P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science who also receives funding from the United Mitochondrial Diseases Foundation, and the EU FP program EUmitocombat and MITOCIRCLE. M.Z. receives support from Fondazione Telethon-Italy (GGP030039) and Fondazione Pierfranco e Luisa Mariani, Italy.
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