Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility

Rovio, Anja T.; Marchington, David R.; Donat, Susanne; Schuppe, H.‐C.; Abel, Josef; Fritsche, Ellen; Elliott, David J.; Laippala, Pekka; Ahola, Arja L.; McNay, David; Harrison, Robert F.; Hughes, Barbara; Barrett, Thomas; Bailey, David M.; Mehmet, Denise; Jequier, Anne M.; Hargreave, T. B.; Kao, Shu Huei; Cummins, James M.; Barton, D. E.; Cooke, Howard J.; Wei, Yau‐Huei; Wichmann, Lars; Poulton, Joanna; Jacobs, Howard T.

doi:10.1038/ng759

Cited by 166 publications

(131 citation statements)

References 15 publications

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“…Results indicated that the studies by Rovio et al, 9 Jensen et al 11 and Harris et al 18 were the main origins of heterogeneity, especially the study by Rovio et al. 9 The heterogeneity changed markedly when this study was omitted ( 23 The shape of the funnel plot revealed no publication bias for all meta-associations ( Figure 4).…”

Section: Polg-cag-repeat Variant and Male Infertility Sy Liu Et Al 301mentioning

confidence: 86%

“…9 The heterogeneity changed markedly when this study was omitted ( 23 The shape of the funnel plot revealed no publication bias for all meta-associations ( Figure 4).…”

Section: Polg-cag-repeat Variant and Male Infertility Sy Liu Et Al 301mentioning

confidence: 95%

“…The results from this study and other casecontrol studies 9,[11][12][13][15][16][17][18][19] were combined for meta-analysis. The departure from HWE for the control group in each study was assessed using a Pearson x 2 test for goodness of fit in the HWE program (http:// ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl).…”

Section: Statistical Analysis and Meta-analysismentioning

confidence: 99%

“…8 Polyglutamine tracts can be sites for protein-protein interactions; altering the tract in POLG may result in suboptimal or improper mtDNA replication. 5 Previous studies have shown that the common allele contains 10 repeats in exon 1 of the POLG gene in European populations (88%) 9 and northern Eurasian populations (88-96%). 10 More and more evidence has indicated that the length of the CAG-repeat may influence the function of spermatozoa, and several studies have confirmed that an alteration in the length of the CAG-repeat is associated with male infertility; 9,11,12 however, some studies have failed to establish such an association.…”

Section: Introductionmentioning

confidence: 99%

“…5 Previous studies have shown that the common allele contains 10 repeats in exon 1 of the POLG gene in European populations (88%) 9 and northern Eurasian populations (88-96%). 10 More and more evidence has indicated that the length of the CAG-repeat may influence the function of spermatozoa, and several studies have confirmed that an alteration in the length of the CAG-repeat is associated with male infertility; 9,11,12 however, some studies have failed to establish such an association. [13][14][15][16][17][18][19] Because there are different distributions of the CAG-repeat length among healthy individuals from different ethnic groups, 10,14,16 a determination of the distribution of CAG-repeat length is necessary before an association study between male infertility and CAG-repeat variants in the POLG gene can be carried out.…”

Section: Introductionmentioning

confidence: 99%

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CAG-repeat variant in the polymerase γ gene and male infertility in the Chinese population: a meta-analysis

Liu¹,

Zhang²,

Haiying³

et al. 2010

Asian J Androl

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Several studies have reported a relationship between the length of the CAG-repeat in the polymerase c (POLG) gene and male infertility. However, other studies have not reproduced this result. In our study, the POLG-CAG-repeat length was analyzed in 535 healthy individuals from six Chinese Han populations living in different provinces. The frequencies of 10-CAG alleles and genotypes were high (97.38 and 94.13%, respectively), with no significant difference among the six Chinese Han populations. Furthermore, we determined the distribution of the POLG-CAG-repeat in 150 infertile men and 126 fertile men. Our study suggested that the distributions of POLG-CAG-repeat alleles and genotypes were not significantly different between infertile (95.67 and 92.67%, respectively) and fertile men (97.22 and 94.44%, respectively). In a subsequent meta-analysis, combining our data with data from previous studies, a comparison of the CAG-repeat alleles in fertile versus infertile men showed no obvious risk for male infertility associated with any particular allele (pooled odds ratio (OR)50.94; 95% confidence interval (CI): 0.60-1.48). The significance level was not attained with any of the following genetic models: homozygote comparison (not 10/not 10 versus 10/10: OR51.34; 95% CI: 0.66-2.72), heterozygote comparison (10/not 10 versus 10/10: OR51.04; 95% CI: 0.78-1.38), dominant model comparison (not 10/not 10110/ not 10 versus 10/10: OR51.08; 95% CI: 0.79-1.47) and recessive genetic comparison (not 10/not 10 versus 10/not 10110/10: OR51.31; 95% CI: 0.68-2.55). In conclusion, there is no significant difference of the frequencies of POLG-CAG-repeat variants among six Chinese Han populations, and this polymorphism may not be associated with Chinese male infertility. On the basis of a meta-analysis, there is no obvious association between CAG-repeat variants of the POLG gene and male infertility.

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Section: Polg-cag-repeat Variant and Male Infertility Sy Liu Et Al 301mentioning

confidence: 86%

“…9 The heterogeneity changed markedly when this study was omitted ( 23 The shape of the funnel plot revealed no publication bias for all meta-associations ( Figure 4).…”

Section: Polg-cag-repeat Variant and Male Infertility Sy Liu Et Al 301mentioning

confidence: 95%

Section: Statistical Analysis and Meta-analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

CAG-repeat variant in the polymerase γ gene and male infertility in the Chinese population: a meta-analysis

Liu¹,

Zhang²,

Haiying³

et al. 2010

Asian J Androl

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Clinical and Genetic Heterogeneity in Progressive External Ophthalmoplegia Due to Mutations in Polymerase γ

Filosto¹,

Mancuso²,

Nishigaki³

et al. 2003

Arch Neurol

106

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Association of Novel POLGMutations and Multiple Mitochondrial DNA Deletions With Variable Clinical Phenotypes in a Spanish Population

González-Vioque¹,

Blázquez²,

Fernández-Moreira³

et al. 2006

Arch Neurol

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Background: Both dominant and recessive mutations were reported in the gene encoding the mitochondrial (mt) DNA polymerase ␥ (POLG) in patients with progressive external ophthalmoplegia (PEO). Phenotypes other than PEO were recently documented in patients with mutations in the POLG gene. Objective: To screen patients with mitochondrial disease and multiple mtDNA deletions in muscle for mutations in the coding regions of the POLG, PEO1, and SLC25A4 genes. Design: To identify the underlying molecular defect in a group of patients with multiple mtDNA deletions comparing their molecular genetic findings with those of healthy controls. Patients: Twenty-four patients (16 men and 8 women) diagnosed with mitochondrial disease and having multiple mtDNA deletions in muscle by Southern blot analysis. Thirteen patients had PEO; 2 had PEO alone, 4 had PEO and myopathy, and 5 had PEO and multisystem involvement. Four patients had multisystem disease without PEO. The remaining 9 patients had isolated myopathy. DNA from 100 healthy individuals was also studied. Results: No mutation was identified in the PEO1 or SLC25A4 genes. Nine POLG mutations were observed in 6 of 24 patients. Four novel mutations were detected and mapped in the linker region (M603L) and in the pol domain of the enzyme (R853W; D1184N; R1146C). Five patients with PEO had mutations: 2 were compound heterozygotes, 1 was homozygous, and another showed a mutation in a single allele. The remaining patient also showed a sole mutation and had an unusual phenotype lacking ocular involvement. Conclusions: POLG molecular defects were found in 25% of our patients with multiple mtDNA deletions and mitochondrial disease. The uncommon phenotype found in 1 of these patients stresses the clinical variability of patients harboring POLG mutations. Molecular studies in the POLG gene should be addressed in patients with mitochondrial disease, particularly in those with PEO, and multiple mtDNA deletions.

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Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility

Cited by 166 publications

References 15 publications

CAG-repeat variant in the polymerase γ gene and male infertility in the Chinese population: a meta-analysis

CAG-repeat variant in the polymerase γ gene and male infertility in the Chinese population: a meta-analysis

Clinical and Genetic Heterogeneity in Progressive External Ophthalmoplegia Due to Mutations in Polymerase γ

Association of Novel POLGMutations and Multiple Mitochondrial DNA Deletions With Variable Clinical Phenotypes in a Spanish Population

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