Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P36969 (phospholipid hydroperoxide glutathione peroxidase)
 344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phospholipid hydroperoxide glutathione peroxidase (PHGPx), the product of gpx-4, is the major selenoprotein in sperm and is considered essential for fertilization because of its multiple roles in spermatogenesis, such as hydroperoxide detoxification, formation of the mitochondrial capsule, and chromatin condensation. Genomic DNA sequences of 3.148 kilobases covering the whole gpx-4 and its flanking regions were amplified from 63 men using the polymerase chain reaction and were analyzed for polymorphisms by direct sequencing. A total of 23 variant sites were detected; 2 were present only in control men (proven fathers; n = 21) and 10 were common to fertile controls and infertile patients (n = 42). A further 11 variant sites were seen in five of the infertile men only. Four of the gpx-4 variants were considered irrelevant to GPx-4-related fertility problems because they occurred homozygously in controls. The majority of the remaining variant sites are also of questionable relevance because they are located in introns or, as third base exchanges, do not affect the protein sequence. However, one of the exon variations leads to an Ala93-Thr exchange that reduces activity in a porcine GPx-4 homologue. Two detected promoter variations were shown by reporter gene constructs to affect transcription in somatic cell lines. These results indicate that gpx-4 polymorphism cannot generally account for the correlation of PHGPx content of sperm and fertility-related parameters, but further examination of this gene as a potential cause of infertility in particular cases is warranted.
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PMID:Genetic variations of gpx-4 and male infertility in humans. 1260 44

The apolipoprotein (apo) E receptor-2 (apoER2) is a member of the low density lipoprotein receptor gene family and an important regulator of neuronal migration. It acts as a receptor for the signaling factor Reelin and provides positional cues to neurons that migrate to their proper position in the developing brain. Besides brain formation defects, apoER2-deficient mice also exhibit male infertility. The role of the receptor in male reproduction, however, remained unclear. Here we demonstrate that apoER2 is highly expressed in the initial segment of the epididymis, where it affects the functional expression of clusterin and phospholipid hydroperoxide glutathione peroxidase (PHGPx), two proteins required for sperm maturation. Reduced PHGPx expression in apoER2 knockout mice results in the inability of the sperm to regulate the cell volume and in abnormal sperm morphology and immotility. Because insufficient expression of PHGPx is a major cause of infertility in men, these findings not only highlight an important new function for apoER2 that is unrelated to neuronal migration, but they also suggest a possible role for apoER2 in human infertility.
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PMID:Essential role of the apolipoprotein E receptor-2 in sperm development. 1269 10

Genetic lesions causing human male infertility are manifold. Besides gross chromosomal aneuploidies and rearrangements, microdeletions and single gene defects can interfere with male fertility. Male fertility is not only dependent on genes controlling the male germ line but also on genes of the networks functional for male gonad development and male somatic development, respectively. It is popular to unravel these netweorks with mouse gene knock-out mutants displaying reproductive defects. However, substantial arguments can be given for more functional studies directly on the human genes, because multiple reproductive proteins evolve quickly most likely for adopting to the specific needs of the species class. Prominent examples are mutations of the FSHR gene causing different pathologies in mouse and human and the DAZ gene family not found in the mouse genome but in the human genome with an essential male fertility function. Therefore this review is focussed on a comprehensive overview of human genes known with mutations causing male infertility (AR; AZF gene families; CFTR, DM-1, DNAH gene family, FGFR1, FSHR, INSL3, KAL-1, LGR8- GREAT, LHR, POLG). Then some human genes are described well recognised as functional in spermatogenesis and male fertility although gene specific mutations causing infertility were not yet identified (CREM, CDY1, DAZL1, PHGPx, PRM-1, PRM-2). They are designated as "spermatogenesis phase marker" or "male fertility index" genes, because they are useful tools for diagnosing the patient's spermatogenesis disruption phase and for predicting the presence and quality of his mature sperms. Current therapeutic protocols for human male infertility do usually not cure the specific gene defect but try to bypass it using Artificial Reproductive Technology (ART). Putative imprinting defects in the early embryo probably associated with the used ART protocol and an increase of chromosome abnormalities in the ART offspring now strongly asks for a significant improvement of this outcome requesting urgently more basic research on the genes functioning in the human male germ line and during early human embryogenesis.
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PMID:Molecular genetics of human male infertility: from genes to new therapeutic perspectives. 1496 34

Excessive production of reactive oxygen species (ROS) may lead to oxidative stress, loss of cell function, and cell death by apoptosis or necrosis. Recently, ROS have gained attention as important second messengers. ROS lifetimes can be very short, and many types of ROS cannot penetrate organelle membranes. It is therefore thought that only ROS signal molecules that are generated locally in an organelle are transduced when cells are stimulated. Lipid hydroperoxides are one type of ROS of which the biological function has not yet been clarified. The phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) is a unique antioxidant enzyme and separately distributed to the mitochondria, nucleus, nucleoli, and cytosol, where it regulates phospholipid hydroperoxide and fatty acid hydroperoxide as signal molecules. This review focuses on the structure and biological functions of PHGPx in mammalian cells. Overexpression of different types of PHGPx in the RBL2H3 cell line provides a useful model system with which to clarify the ability of different types of PHGPx to modulate cellular function and the importance of lipid hydroperoxides as signal molecules. Transformant studies show that lipid hydroperoxide is an activator of lipoxygenase and cyclooxygenase and participates in inflammation, cardiolipin hydroperoxide is the signal molecule for the release of cytochrome c during apoptotic cell death, and PHGPx is a signal regulator in the IgE receptor-mediated signaling pathway. It is becoming clear that PHGPx has an important role in spermatogenesis, sperm function, and embryonic development, and its deficiency is implicated in human infertility and in embryonic lethality of PHGPx knockout mice.
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PMID:[Biological significance of lipid hydroperoxide and its reducing enzyme, phospholipid hydroperoxide glutathione peroxidase, in mammalian cells]. 1557 64

The role of selenium in male fertility is reviewed with special emphasis on selenoprotein P and phospholipid hydroperoxide glutathione peroxidase (GPx4) in spermiogenesis. Inverse genetics reveal that selenoprotein P is required for selenium supply to the testis. GPx4 is abundantly synthesized in spermatids. As a moonlighting protein it is transformed in the later stages of spermiogenesis from an active selenoperoxidase into a structural protein that becomes a constituent of the mitochondrial sheath of spermatozoa. The transformation is paralleled by loss of glutathione. Mechanistically, the process is an alternate substrate inactivation of GPx4 resulting from reactions of its selenenic form with thiols of GPx4 itself and other proteins. Circumstantial evidence and ongoing experimental genetics indicate that the mitochondrially expressed form of the GPx4 gene is the most relevant one in spermiogenesis, with the nuclear form being dispensable for fertility and the role of cytosolic GPx4 remaining unclear. Clinical data reveal a strong association of low sperm GPx4 with infertility. Thus, impaired GPx4 biosynthesis, due to selenium deficiency or to genetic defects in gpx4 itself or in proteins involved in Se distribution and selenoprotein biosynthesis, causes male infertility, but can also be an epiphenomenon due to any perturbation of testicular function.
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PMID:Selenium in mammalian spermiogenesis. 1793 12