The polymorphic polyglutamine repeat in the mitochondrial DNA polymerase γ gene is not associated with oligozoospermia

Università degli Studi di Torino, Torino, Piedmont, Italy
Journal of endocrinological investigation (Impact Factor: 1.45). 02/2006; 29(1):1-4. DOI: 10.1007/BF03349169
Source: PubMed


The POLG1 nuclear gene, encoding for the catalytic subunit of the mitochondrial polymerase gamma, has been reported to play a role in male infertility. In fact, genotypes showing alleles different from the common ten repeat CAG allele have been detected in patients with oligozoospermia or in patients with normal spermiograms and unexplained infertility. However, these results have been debated by other studies. To verify these data, we analyzed 625 individuals in three groups of case-controls from three different Italian regions. In these series, the frequency of the different genotypes was not statistically different in oligozoospermic vs normal subjects. Even considering the pooled controls and patients (348 and 277, respectively), no significant difference was shown (p = 0.11). Our findings, in agreement with other studies from Italy and France, suggest that, at least in these countries, the POLG1 CAG-repeat polymorphisms do not contribute to oligozoospermia.

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    • "More precisely, men with reduced semen quality more often had a not10/not10 CAG-repeat genotype as compared to men with normal semen quality and male partners from subfertile couples (regardless of their semen quality) more often had this not10/not10 genotype than males partners from fertile couples. Since this initial publication, five studies have assessed the association between the not10/not10 CAG-repeat variant in POLG and male subfertility and/or spermatogenic failure with conflicting results (Table I) (Jensen et al., 2004; Krausz et al., 2004; Aknin-Seifer et al., 2005; Brusco et al., 2006; Harris et al., 2006). These conflicting results may be due to the case –control design used in these studies, which is prone to selection bias. "
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    ABSTRACT: Several case–control studies have investigated the effect of CAG repeat length variation in the POLG gene on male fertility and semen quality. Some described an association between the homozygous not10 CAG-repeat genotype and male subfertility and/or reduced semen quality, whereas others did not. The aim of our study was to investigate whether the not10/not10 variant is associated with spermatogenic failure. By direct sequencing methods, we determined the CAG repeat length of POLG in a cohort of 700 consecutive included men with variable degrees of spermatogenesis to investigate its effect on semen quality. The frequency of the not10/not10 variant in our cohort was 4.7%. There were no differences in semen quality between groups with various POLG genotypes. There was a significant difference in frequency of the three CAG-repeat genotypes between ethnic subgroups. In conclusion, the not10/not10 POLG variant is not associated with clinically significant decreases in semen quality, but its frequency is dependent on ethnic background.
    Full-text · Article · May 2008 · Molecular Human Reproduction
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    • "To this extent, two studies have demonstrated an association between the absence of the common allele and male infertility, typified by a range of sperm quality defects, (Rovio et al., 2001) and idiopathic subfertility (Jensen et al., 2004). However, this association was not identified in populations of Italian (Krausz et al., 2004; Brusco et al., 2006) and French (Aknin-Seifer et al., 2005) subfertile men. Our results do not show an association between each of the three principal semen parameters, when assessed independently , and POLG genotypes, which is in agreement with Krausz et al. (2004) and Aknin-Seifer et al. (2005). "
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    ABSTRACT: Human mitochondrial DNA (mtDNA) encodes 13 polypeptides of the electron transfer chain. Its replication is dependent on the nuclear-encoded polymerase gamma (POLG) and mitochondrial transcription factor A (TFAM). For POLG, only the polyglutamine tract, characterized by a series of CAG repeats, has been investigated in human sperm. However, TFAM is associated with the reduction in mtDNA content of testicular sperm. We have determined whether POLG and TFAM have functional roles in post-ejaculatory sperm mtDNA. Sperm samples were categorized as: normals, samples with one or two abnormal sperm parameters and oligoasthenoteratozoospermics (OATs). These were analysed by fluorescent PCR to determine the number of CAG repeats, real-time PCR for mtDNA copy number and immunocytochemistry and western blotting for patterns of expression for POLG, TFAM and the mtDNA-encoded COXI. Only the OAT group presented with a significantly higher incidence of heterozygosity for CAG repeats, higher mtDNA content and a lower percentage of sperm expressing POLG and TFAM. Paradoxically, good-quality sperm had fewer mtDNA copies but significantly more sperm expressed POLG, TFAM and COXI. Our data support the original findings that an association between sperm quality and POLG CAG repeats does exist. However, the biological significance of these variants in male infertility remains unclear, as these do not seem to affect mtDNA maintenance. The reduction in mtDNA content in normal samples likely reflects normal spermiogenesis, whereas increases in POLG and TFAM expression possibly compensate for the low mtDNA content, maintaining mitochondrial homeostasis.
    Full-text · Article · Jul 2007 · Human Reproduction
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    ABSTRACT: Thesis focuses on mutations of POLG1 gene encoding catalytic subunit polγ-α of mitochondrial DNA polymerase gamma holoenzyme (polG) and the association of mutations with different clinical phenotypes. In addition, particular defective mutant variants of the protein were characterized biochemically in vitro. PolG-holoenzyme is the sole DNA polymerase found in mitochondria. It is involved in replication and repair of the mitochondrial genome, mtDNA. Holoenzyme also includes the accessory subunit polγ-β, which is required for the enhanced processivity of polγ-α. Defective polγ-α causes accumulation of secondary mutations on mtDNA, which leads to a defective oxidative phosphorylation system. The clinical consequences of such mutations are variable, affecting nervous system, skeletal muscles, liver and other post-mitotic tissues. The aims of the studies included: 1) Determination of the role of POLG1 mutations in neurological syndromes with features of mitochondrial dysfunction and an unknown molecular cause. 2) Development and set up of diagnostic tests for routine clinical purposes. 3) Biochemical characterization of the functional consequences of the identified polγ-α variants. Studies describe new neurological phenotypes in addition to PEO caused by POLG1 mutations, including parkinsonism, premature amenorrhea, ataxia and Parkinson s disease (PD). POLG1 mutations and polymorphisms are both common and/or potential genetic risk factors at least among the Finnish population. The major findings and applications reported here are: 1) POLG1 mutations cause parkinsonism and premature menopause in PEO families in either a recessive or a dominant manner. 2) A common recessive POLG1 mutations (A467T and W748S) in the homozygous state causes severe adult or juvenile-onset ataxia without muscular symptoms or histological or mtDNA abnormalities in muscles. 3) A common recessive pathogenic change A467T can also cause a mild dominant disease in heterozygote carriers. 4) The A467T variant shows reduced polymerase activity due to defective template binding. 5) Rare polyglutamine tract length variants of POLG1 are significantly enriched in Finnish idiopathic Parkinson s disease patients. 6) Dominant mutations are clearly restricted to the highly conserved polymerase domain motifs, whereas recessive ones are more evenly distributed along the protein. The present results highlight and confirm the new role of mitochondria in parkinsonism/Parkinson s disease and describe a new mitochondrial ataxia. Based on these results, a POLG1 diagnostic routine has been set up in Helsinki University Central Hospital (HUSLAB). Ihmisen perintötekijät eli geenit sijaitsevat lähes yksinomaan solujen tumassa. Niiden määräksi on ihmisellä arvioitu noin 20-30 000. Vain 37 näistä geeneistä sijaitsee tuman ulkopuolella solujen mitokondrioissa, joita usein kuvataan solujen voimalaitoksiksi . Niiden tärkeimpänä tehtävänä on muuntaa ravintoaineiden kemiallinen energia yhdenmukaiseen muotoon, polttoaineeksi eli ATP:ksi, jota solujen rakentamiseen ja ylläpitoon osallistuvat entsyymit voivat yleisesti käyttää. Tässä muutostyössä hapella on tärkeä rooli, puhumme soluhengityksestä. Kun soluhengitys ei toimi kunnolla, lisääntyy soluissa myös hapen vahingolliset muodot aiheuttaen solurakenteiden vaurioitumista. Kuten tuman geeneistä, myös mitokondrioissa olevista geeneistä täytyy pitää huolta: monistaa ja korjata vaurioita. Tässä työssä keskeisimpiä entsyymejä on DNA polymeraasi gamma. Kuten tiedämme, voi yhden ainoan geenin yksi virhe tuottaa vakavan sairauden ihmisessä, näin on asian laita myös DNA polymeraasi gamman kohdalla. Erona kuitenkin useimpien muiden geenien mutaatioihin nähden on se, että DNA polymeraasi gamman mutaatiot saavat aikaan lisää mutaatioita niissä 37:ssä geenissä, jotka ovat mitokondrioiden sisällä. Koska kyseiset geenit ovat tärkeitä soluhengityksen kannalta, aiheuttaa niiden vaurioituminen ongelmia soluhengitykselle ja energia-aineenvaihdunnalle ja tästä koituu vakavia seurauksia ihmiselle. Tässä väitöstyössä kuvataan uusia DNA polymeraasi gamman mutaatioita ja niihin liittyviä sairauksia, joista tärkeimpinä ataksia sekä Parkinsonin tauti. Työssä mm. kuvataan uusi mutaatio, joka on osoittautunut yleisimmäksi ataksian aiheuttajaksi Suomessa. Sen lisäksi työssä osoitettiin DNA polymeraasi gammalla olevan yleisimmän päätyypin lisäksi ainakin 17 erilaista alatyyppiä suomalaisessa väestössä. Osan näistä harvinaisista DNA polymeraasi gamman alatyypeistä osoitettiin olevan taustalla huomattavalla määrällä suomalaisista Parkinsonin tautia sairastavista. DNA polymeraasi gamma saattaa osoittautua yleisimmäksi tautigeeniksi Parkinsonin taudin taustalla Suomessa. Tulokset vahvistavat osaltaan mitokondrioiden tärkeää roolia kyseisissä sairauksissa. Tärkeänä havaintona voidaan myös pitää sitä että sama mutaatio eri perheissä saattaa aiheuttaa joko vallitsevasti tai peittyvästi periytyvän taudin. Vallitsevasti periytyvässä taudissa yksi, esimerkiksi äidiltä periytyvässä geenissä oleva mutaatio aiheuttaa yksinään sairauden. Peittyvästi periytyvässä sairaudessa tarvitaan sekä isältä että äidiltä peritystä geenistä mutatoitunut muoto. Näiden tutkimustulosten pohjalta on saatu tärkeää tietoa neurologisten sairauksien molekulaarisista mekanismeista sekä luotu Helsingin yliopistolliseen keskussairaalaan uusia diagnostisia menetelmiä, sekä tietoa jota voidaan soveltaa perinnöllisyysneuvonnassa.
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