24 results on '"Heijden, G.W. van der"'
Search Results
2. High fat diet-induced obesity prolongs critical stages of the spermatogenic cycle in a Ldlr(-/-).Leiden mouse model
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Komninos, D., Ramos, L., Heijden, G.W. van der, Morrison, M.C., Kleemann, R., Herwaarden, A.E. van, Kiliaan, A.J., Arnoldussen, I.A.C., Komninos, D., Ramos, L., Heijden, G.W. van der, Morrison, M.C., Kleemann, R., Herwaarden, A.E. van, Kiliaan, A.J., and Arnoldussen, I.A.C.
- Abstract
Item does not contain fulltext
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- 2022
3. A de novo paradigm for male infertility
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Oud, M.S., Smits, R.M., Smith, H.E., Mastrorosa, F.K., Holt, G.S., Houston, B.J., Vries, P.F. de, Alobaidi, B.K.S., Batty, L.E., Ismail, H., Greenwood, J., Sheth, H., Mikulasova, A., Astuti, G.D.N, Gilissen, C., McEleny, K., Turner, H., Coxhead, J., Cockell, S., Braat, D.D.M., Fleischer, K., D'Hauwers, K.W.M., Schaafsma, E., Nagirnaja, L., Conrad, D.F., Friedrich, C., Kliesch, S., Aston, K.I., Riera-Escamilla, A., Krausz, C., Gonzaga-Jauregui, C., Santibanez-Koref, M., Elliott, D.J., Vissers, L.E.L.M., Tüttelmann, F., O'Bryan, M.K., Ramos, L., Xavier, M.J., Heijden, G.W. van der, Veltman, J.A., Oud, M.S., Smits, R.M., Smith, H.E., Mastrorosa, F.K., Holt, G.S., Houston, B.J., Vries, P.F. de, Alobaidi, B.K.S., Batty, L.E., Ismail, H., Greenwood, J., Sheth, H., Mikulasova, A., Astuti, G.D.N, Gilissen, C., McEleny, K., Turner, H., Coxhead, J., Cockell, S., Braat, D.D.M., Fleischer, K., D'Hauwers, K.W.M., Schaafsma, E., Nagirnaja, L., Conrad, D.F., Friedrich, C., Kliesch, S., Aston, K.I., Riera-Escamilla, A., Krausz, C., Gonzaga-Jauregui, C., Santibanez-Koref, M., Elliott, D.J., Vissers, L.E.L.M., Tüttelmann, F., O'Bryan, M.K., Ramos, L., Xavier, M.J., Heijden, G.W. van der, and Veltman, J.A.
- Abstract
Item does not contain fulltext, De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10(-5)) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10(-4)) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.
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- 2022
4. Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure
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Riera-Escamilla, A., Vockel, M., Nagirnaja, L., Xavier, M.J., Carbonell, A., Moreno-Mendoza, D., Pybus, M., Farnetani, G., Rosta, V., Cioppi, F., Friedrich, C., Oud, M.S., Heijden, G.W. van der, Soave, A., Diemer, T., Ars, E., Sánchez-Curbelo, J., Kliesch, S., O'Bryan, M.K., Ruiz-Castañe, E., Azorín, F., Veltman, J.A., Aston, K.I., Conrad, D.F., Tüttelmann, F., Krausz, C., Riera-Escamilla, A., Vockel, M., Nagirnaja, L., Xavier, M.J., Carbonell, A., Moreno-Mendoza, D., Pybus, M., Farnetani, G., Rosta, V., Cioppi, F., Friedrich, C., Oud, M.S., Heijden, G.W. van der, Soave, A., Diemer, T., Ars, E., Sánchez-Curbelo, J., Kliesch, S., O'Bryan, M.K., Ruiz-Castañe, E., Azorín, F., Veltman, J.A., Aston, K.I., Conrad, D.F., Tüttelmann, F., and Krausz, C.
- Abstract
Item does not contain fulltext, Although the evolutionary history of the X chromosome indicates its specialization in male fitness, its role in spermatogenesis has largely been unexplored. Currently only three X chromosome genes are considered of moderate-definitive diagnostic value. We aimed to provide a comprehensive analysis of all X chromosome-linked protein-coding genes in 2,354 azoospermic/cryptozoospermic men from four independent cohorts. Genomic data were analyzed and compared with data in normozoospermic control individuals and gnomAD. While updating the clinical significance of known genes, we propose 21 recurrently mutated genes strongly associated with and 34 moderately associated with azoospermia/cryptozoospermia not previously linked to male infertility (novel). The most frequently affected prioritized gene, RBBP7, was found mutated in ten men across all cohorts, and our functional studies in Drosophila support its role in germ stem cell maintenance. Collectively, our study represents a significant step towards the definition of the missing genetic etiology in idiopathic severe spermatogenic failure and significantly reduces the knowledge gap of X-linked genetic causes of azoospermia/cryptozoospermia contributing to the development of future diagnostic gene panels.
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- 2022
5. The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans
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Wyrwoll, M.J., Gaasbeek, Channah M., Golubickaite, I., Stakaitis, R., Oud, M.S., Nagirnaja, L., Dion, C., Sindi, E.B., Leitch, H.G., Jayasena, C.N., Sironen, A., Dicke, A.K., Rotte, N., Stallmeyer, B., Kliesch, S., Grangeiro, C.H.P., Araujo, T.F., Lasko, P.F., D'Hauwers, K.W., Smits, R.M., Ramos, L., Xavier, M.J., Conrad, D.F., Almstrup, K., Veltman, J.A., Tüttelmann, F., Heijden, G.W. van der, Wyrwoll, M.J., Gaasbeek, Channah M., Golubickaite, I., Stakaitis, R., Oud, M.S., Nagirnaja, L., Dion, C., Sindi, E.B., Leitch, H.G., Jayasena, C.N., Sironen, A., Dicke, A.K., Rotte, N., Stallmeyer, B., Kliesch, S., Grangeiro, C.H.P., Araujo, T.F., Lasko, P.F., D'Hauwers, K.W., Smits, R.M., Ramos, L., Xavier, M.J., Conrad, D.F., Almstrup, K., Veltman, J.A., Tüttelmann, F., and Heijden, G.W. van der
- Abstract
Contains fulltext : 282942.pdf (Publisher’s version ) (Open Access), Infertility affects around 7% of the male population and can be due to severe spermatogenic failure (SPGF), resulting in no or very few sperm in the ejaculate. We initially identified a homozygous frameshift variant in FKBP6 in a man with extreme oligozoospermia. Subsequently, we screened a total of 2,699 men with SPGF and detected rare bi-allelic loss-of-function variants in FKBP6 in five additional persons. All six individuals had no or extremely few sperm in the ejaculate, which were not suitable for medically assisted reproduction. Evaluation of testicular tissue revealed an arrest at the stage of round spermatids. Lack of FKBP6 expression in the testis was confirmed by RT-qPCR and immunofluorescence staining. In mice, Fkbp6 is essential for spermatogenesis and has been described as being involved in piRNA biogenesis and formation of the synaptonemal complex (SC). We did not detect FKBP6 as part of the SC in normal human spermatocytes, but small RNA sequencing revealed that loss of FKBP6 severely impacted piRNA levels, supporting a role for FKBP6 in piRNA biogenesis in humans. In contrast to findings in piRNA-pathway mouse models, we did not detect an increase in LINE-1 expression in men with pathogenic FKBP6 variants. Based on our findings, FKBP6 reaches a "strong" level of evidence for being associated with male infertility according to the ClinGen criteria, making it directly applicable for clinical diagnostics. This will improve patient care by providing a causal diagnosis and will help to predict chances for successful surgical sperm retrieval.
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- 2022
6. Variant PNLDC1, Defective piRNA Processing, and Azoospermia
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Nagirnaja, L., Mørup, N., Nielsen, J.E., Stakaitis, R., Golubickaite, I., Oud, M.S., Winge, S.B., Carvalho, F., Aston, K.I., Khani, F., Heijden, G.W. van der, Marques, C.J., Skakkebaek, N.E., Rajpert-De Meyts, E., Schlegel, P.N., Jørgensen, N., Veltman, J.A., Lopes, A.M., Conrad, D.F., Almstrup, K., Nagirnaja, L., Mørup, N., Nielsen, J.E., Stakaitis, R., Golubickaite, I., Oud, M.S., Winge, S.B., Carvalho, F., Aston, K.I., Khani, F., Heijden, G.W. van der, Marques, C.J., Skakkebaek, N.E., Rajpert-De Meyts, E., Schlegel, P.N., Jørgensen, N., Veltman, J.A., Lopes, A.M., Conrad, D.F., and Almstrup, K.
- Abstract
Item does not contain fulltext, BACKGROUND: P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are short (21 to 35 nucleotides in length) and noncoding and are found almost exclusively in germ cells, where they regulate aberrant expression of transposable elements and postmeiotic gene expression. Critical to the processing of piRNAs is the protein poly(A)-specific RNase-like domain containing 1 (PNLDC1), which trims their 3' ends and, when disrupted in mice, causes azoospermia and male infertility. METHODS: We performed exome sequencing on DNA samples from 924 men who had received a diagnosis of nonobstructive azoospermia. Testicular-biopsy samples were analyzed by means of histologic and immunohistochemical tests, in situ hybridization, reverse-transcriptase-quantitative-polymerase-chain-reaction assay, and small-RNA sequencing. RESULTS: Four unrelated men of Middle Eastern descent who had nonobstructive azoospermia were found to carry mutations in PNLDC1: the first patient had a biallelic stop-gain mutation, p.R452Ter (rs200629089; minor allele frequency, 0.00004); the second, a novel biallelic missense variant, p.P84S; the third, two compound heterozygous mutations consisting of p.M259T (rs141903829; minor allele frequency, 0.0007) and p.L35PfsTer3 (rs754159168; minor allele frequency, 0.00004); and the fourth, a novel biallelic canonical splice acceptor site variant, c.607-2A→T. Testicular histologic findings consistently showed error-prone meiosis and spermatogenic arrest with round spermatids of type Sa as the most advanced population of germ cells. Gene and protein expression of PNLDC1, as well as the piRNA-processing proteins PIWIL1, PIWIL4, MYBL1, and TDRKH, were greatly diminished in cells of the testes. Furthermore, the length distribution of piRNAs and the number of pachytene piRNAs was significantly altered in men carrying PNLDC1 mutations. CONCLUSIONS: Our results suggest a direct mechanistic effect of faulty piRNA processing on meiosis and spermatogenesis in men, ultima
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- 2021
7. Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility
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Wyrwoll, Margot J., Temel, Sehime G., Nagirnaja, Liina, Oud, M.S., Lopes, Alexandra M., Heijden, G.W. van der, Smits, R.M., Veltman, J.A., Friedrich, Corinna, Tuettelmann, Frank, Wyrwoll, Margot J., Temel, Sehime G., Nagirnaja, Liina, Oud, M.S., Lopes, Alexandra M., Heijden, G.W. van der, Smits, R.M., Veltman, J.A., Friedrich, Corinna, and Tuettelmann, Frank
- Abstract
Contains fulltext : 221672.pdf (Publisher’s version ) (Open Access)
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- 2020
8. Transmission of modified nucleosomes from the mouse male germline to the zygote and subsequent remodeling of paternal chromatin
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Heijden, G.W. van der, Derijck, A.A.H.A., Ramos, L., Giele, M., Vlag, J. van der, and Boer, P. de
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Chromatin -- Research ,Fertilization (Biology) -- Research ,Mice -- Research ,Biological sciences - Abstract
A study on paternal chromatin content directly after gamete fusion and the transference of nucleosomes from male germ line to zygote in mice is studied.
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- 2006
9. The transmission of chromatin and DNA lesions by sperm and their fate in the zygote
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Heijden, G.W. van der, Kremer, J.A.M., Boer, P. de, and Radboud University Nijmegen
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Endocrinology and reproduction [UMCN 5.2] - Abstract
Item does not contain fulltext RU Radboud Universiteit Nijmegen, 01 november 2007 Promotor : Kremer, J.A.M. Co-promotor : Boer, P. de
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- 2007
10. In vivo repair of DNA damage induced by X-rays in the early stages of mouse fertilization, and the influence of maternal PARP1 ablation.
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Pacchierotti, F., Ranaldi, R., Derijck, A.H.A., Heijden, G.W. van der, Boer, P. de, Pacchierotti, F., Ranaldi, R., Derijck, A.H.A., Heijden, G.W. van der, and Boer, P. de
- Abstract
Item does not contain fulltext, The early pronucleus stage of the mouse zygote has been characterised in vitro as radiosensitive, due to a high rate of induction of chromosome-type chromosome abnormalities (CA). We have investigated the repair of irradiation induced double strand DNA breaks in vivo by γH2AX foci and first cleavage metaphase analysis. Breaks were induced in sperm and in the early zygote stages comprising sperm chromatin remodelling and early pronucleus expansion. Moreover, the role of PARP1 in the formation and repair of spontaneous and radiation-induced double strand breaks in the zygote was evaluated by comparing observations in C57BL/6J and PARP1 genetically ablated females. The results confirmed in vivo that the rate of chromosome aberration induction by X-rays was approximately 3-fold higher in the zygote than in mouse lymphocytes. This finding was related to a diminished efficiency of double strand break signalling, as shown by a lower rate of γH2AX radiation-induced foci compared to that measured in most other somatic cell types. The spontaneous frequency of CA in PARP1 depleted zygotes was slightly but significantly higher than in wild type zygotes. Also, these zygotes showed some impairment of the radiation-induced DNA Damage Response when exposed closer to the start of S-phase, revealed by a higher number of γH2AX foci and a longer cell cycle delay. The rate of chromosome aberrations, however, was not elevated over that of wild type zygotes, possibly thanks to backup repair pathways and/or selection mechanisms against damaged cells. When comparing with the literature data on irradiation induced CA in mouse zygotes in vitro, the levels of induction were strikingly similar as was the frequency of misrepair of double strand breaks (γH2AX foci). This result can be reassuring for in vitro human gamete and embryo handling, because it shows that culture conditions do not significantly affect double strand DNA break repair.
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- 2011
11. Parental origin of chromatin in human monopronuclear zygotes revealed by asymmetric histone methylation patterns, differs between IVF and ICSI.
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Heijden, G.W. van der, Berg, I.M. van den, Baart, E.B., Derijck, A.H.A., Martini, E., Boer, P. de, Heijden, G.W. van der, Berg, I.M. van den, Baart, E.B., Derijck, A.H.A., Martini, E., and Boer, P. de
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Contains fulltext : 81811.pdf (publisher's version ) (Closed access), In mouse zygotes, many post-translational histone modifications are asymmetrically present in male and female pronuclei. We investigated whether this principle could be used to determine the genetic composition of monopronuclear human zygotes in conventional IVF and ICSI. First we determined whether male female asymmetry is conserved from mouse to human by staining polypronuclear zygotes with antibodies against a subset of histone N-tail post-translational modifications. To analyze human monopronuclear zygotes, a modification, H3K9me3, was selected that is present in the maternal chromatin. After IVF a total of 45 monopronuclear zygotes were obtained. In 39 (87%) of zygotes a nonuniform staining pattern was observed, proof of a bi-parental origin and assumed to result into a diploid conception. Two zygotes showed no staining for the modification, indicating that the single pronucleus was of paternal origin. Four zygotes contained only maternally derived chromatin. ICSI-derived monopronuclear zygotes (n = 33) could also be divided into three groups based on the staining pattern of their chromatin: (1) of maternal origin (n = 15), (2) of paternal origin (n = 8) or (3) consisting of two chromatin domains as dominating in IVF (n = 10). Our data show that monopronuclear zygotes originating from IVF generally arise through fusion of parental chromatin after sperm penetration. Monopronuclear zygotes derived from ICSI in most cases contain uni-parental chromatin. The fact that chromatin was of paternal origin in 24% of ICSI and in 4% of the IVF zygotes confirms earlier results obtained by FISH on cleavage stages. Our findings are of clinical importance in IVF and ICSI practice.
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- 2009
12. Sperm-derived histones contribute to zygotic chromatin in humans.
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Heijden, G.W. van der, Ramos, L., Baart, E.B., Berg, I.M. van den, Derijck, A.H.A., Vlag, J. van der, Martini, E., Boer, P. de, Heijden, G.W. van der, Ramos, L., Baart, E.B., Berg, I.M. van den, Derijck, A.H.A., Vlag, J. van der, Martini, E., and Boer, P. de
- Abstract
Contains fulltext : 70968.pdf ( ) (Open Access), BACKGROUND: about 15% to 30% of the DNA in human sperm is packed in nucleosomes and transmission of this fraction to the embryo potentially serves as a mechanism to facilitate paternal epigenetic programs during embryonic development. However, hitherto it has not been established whether these nucleosomes are removed like the protamines or indeed contribute to paternal zygotic chromatin, thereby potentially contributing to the epigenome of the embryo. RESULTS: to clarify the fate of sperm-derived nucleosomes we have used the deposition characteristics of histone H3 variants from which follows that H3 replication variants present in zygotic paternal chromatin prior to S-phase originate from sperm. We have performed heterologous ICSI by injecting human sperm into mouse oocytes. Probing these zygotes with an antibody highly specific for the H3.1/H3.2 replication variants showed a clear signal in the decondensed human sperm chromatin prior to S-phase. In addition, staining of human multipronuclear zygotes also showed the H3.1/H3.2 replication variants in paternal chromatin prior to DNA replication. CONCLUSION: these findings reveal that sperm-derived nucleosomal chromatin contributes to paternal zygotic chromatin, potentially serving as a template for replication, when epigenetic information can be copied. Hence, the execution of epigenetic programs originating from transmitted paternal chromatin during subsequent embryonic development is a logical consequence of this observation.
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- 2008
13. Incomplete nuclear transformation of human spermatozoa in oligo-astheno-teratospermia: characterization by indirect immunofluorescence of chromatin and thiol status.
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Ramos, L., Heijden, G.W. van der, Derijck, A.H.A., Berden, J.H.M., Kremer, J.A.M., Vlag, J. van der, Boer, P. de, Ramos, L., Heijden, G.W. van der, Derijck, A.H.A., Berden, J.H.M., Kremer, J.A.M., Vlag, J. van der, and Boer, P. de
- Abstract
Contains fulltext : 69766.pdf (publisher's version ) (Open Access), BACKGROUND Sperm heterogeneity in the human, as observed in oligo-astheno-teratozoospermia (OAT), is associated with hypospermatogenesis. METHODS The chromatin of sperm from OAT and normospermic males was characterized with antibodies specific for nucleosomes, the histone H3.1/H3.2 isoform, histone TH2B, apoptosis-associated H4 acetylation (KM-2) and protamines. Subsequently, sperm samples were stained with the thiol-specific fluorochrome monobromobimane (mBBr) before and after reduction with dithiotreitol (DTT) as most thiol groups reside in the cysteine-rich protamines. We also used fluorescence-activated cell sorter (FACS) for sperm histograms and sorting for high or low free and total thiol levels. These fractions were further analysed for DNA damage with the TdT-UTP nick end-labelling (TUNEL) assay. RESULTS OAT sperm nuclei stained higher for nucleosomes and KM2-epitopes, and lower for TH2B. For free, and total, thiol groups, OAT sperm were characterized by biphasic distributions, reflecting incomplete thiol oxidation as well as overoxidation, and possibly reduced protamine contents. The TUNEL assay on sperm subfractions, for both control and OAT sperm, revealed that a lower level of free thiol groups is associated with a higher TUNEL incidence, and this relationship was also found for total thiol levels. Hence, both overoxidation and a low total number of thiol groups predestine for sperm apoptosis. CONCLUSIONS Chromatin characteristics reflecting an incomplete nucleosome to protamine remodelling were found in subfertile males. Sperm apoptosis is related to both incomplete remodelling and protamine overoxidation.
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- 2008
14. Mouse maelstrom, a component of nuage, is essential for spermatogenesis and transposon repression in meiosis.
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Soper, S.F., Heijden, G.W. van der, Hardiman, T.C., Goodheart, M., Martin, S.L., Boer, P. de, Bortvin, A., Soper, S.F., Heijden, G.W. van der, Hardiman, T.C., Goodheart, M., Martin, S.L., Boer, P. de, and Bortvin, A.
- Abstract
Contains fulltext : 70649.pdf (publisher's version ) (Closed access), Tight control of transposon activity is essential for the integrity of the germline. Recently, a germ-cell-specific organelle, nuage, was proposed to play a role in transposon repression. To test this hypothesis, we disrupted a murine homolog of a Drosophila nuage protein Maelstrom. Effects on male meiotic chromosome synapsis and derepression of transposable elements (TEs) were observed. In the adult Mael(-/-) testes, LINE-1 (L1) derepression occurred at the onset of meiosis. As a result, Mael(-/-) spermatocytes were flooded with L1 ribonucleoproteins (RNPs) that accumulated in large cytoplasmic enclaves and nuclei. Mael(-/-) spermatocytes with nuclear L1 RNPs exhibited massive DNA damage and severe chromosome asynapsis even in the absence of SPO11-generated meiotic double-strand breaks. This study demonstrates that MAEL, a nuage component, is indispensable for the silencing of TEs and identifies the initiation of meiosis as an important step in TE control in the male germline.
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- 2008
15. Motile human normozoospermic and oligozoospermic semen samples show a difference in double-strand DNA break incidence.
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Derijck, A.H.A., Heijden, G.W. van der, Ramos, L., Giele, M.M., Kremer, J.A.M., Boer, P. de, Derijck, A.H.A., Heijden, G.W. van der, Ramos, L., Giele, M.M., Kremer, J.A.M., and Boer, P. de
- Abstract
Contains fulltext : 53507.pdf (publisher's version ) (Closed access), BACKGROUND: Among ICSI children de novo structural chromosome aberrations of male descent are increased. Misrepair of double-strand DNA breaks (DSBs) is a prerequisite for such aberrations to occur. To date, no absolute assessment of the number of DSBs in human sperm nuclei after gamete fusion has been described. METHODS: Using man-mouse heterologous ICSI and gammaH2AX immunofluorescent staining, capable of detecting a single DSB, the number of lesions in ICSI selected sperm from normozoospermic men (n = 2) and oligozoospermic patients (n = 3) was quantified. A comparison with a subfertile male mouse model (n = 5) has been made. In addition, the fate of morphologically normal ejaculated immotile sperm after ICSI was examined. RESULTS: A significant increase in the fraction of sperm cells bearing DSBs was found in oligozoospermic semen compared with that from normozoospermic men (P < 0.01). The majority of morphologically normal immotile human sperm showed excess gammaH2AX staining and nuclear disintegration. However, some had a non-deviant DSB pattern. CONCLUSIONS: The increased fraction of DSB-positive sperm in both human and mouse oligozoospermic semen is adding to the surmise that semen from oligozoospermic patients has a reduced chromatin quality, causally related to reduced preimplantation embryo development. The use of ejaculated immotile sperm for in vitro reproduction is debatable due to sperm DNA degradation.
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- 2007
16. The transmission of chromatin and DNA lesions by sperm and their fate in the zygote.
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Kremer, J.A.M., Boer, P. de, Heijden, G.W. van der, Kremer, J.A.M., Boer, P. de, and Heijden, G.W. van der
- Abstract
RU Radboud Universiteit Nijmegen, 1 november 2007, Promotor : Kremer, J.A.M. Co-promotor : Boer, P. de, Item does not contain fulltext
- Published
- 2007
17. Chromosome-wide nucleosome replacement and H3.3 incorporation during mammalian meiotic sex chromosome inactivation.
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Heijden, G.W. van der, Derijck, A.H.A., Posfai, E., Giele, M.M., Pelczar, P., Ramos, L., Wansink, D.G., Vlag, J. van der, Peters, A.H., Boer, P. de, Heijden, G.W. van der, Derijck, A.H.A., Posfai, E., Giele, M.M., Pelczar, P., Ramos, L., Wansink, D.G., Vlag, J. van der, Peters, A.H., and Boer, P. de
- Abstract
Contains fulltext : 52236.pdf (publisher's version ) (Closed access), In mammalian males, the first meiotic prophase is characterized by formation of a separate chromatin domain called the sex body. In this domain, the X and Y chromosomes are partially synapsed and transcriptionally silenced, a process termed meiotic sex-chromosome inactivation (MSCI). Likewise, unsynapsed autosomal chromatin present during pachytene is also silenced (meiotic silencing of unsynapsed chromatin, MSUC). Although it is known that MSCI and MSUC are both dependent on histone H2A.X phosphorylation mediated by the kinase ATR, and cause repressive H3 Lys9 dimethylation, the mechanisms underlying silencing are largely unidentified. Here, we demonstrate an extensive replacement of nucleosomes within unsynapsed chromatin, depending on and initiated shortly after induction of MSCI and MSUC. Nucleosomal eviction results in the exclusive incorporation of the H3.3 variant, which to date has primarily been associated with transcriptional activity. Nucleosomal exchange causes loss and subsequent selective reacquisition of specific histone modifications. This process therefore provides a means for epigenetic reprogramming of sex chromatin presumably required for gene silencing in the male mammalian germ line.
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- 2007
18. Maternal effects of the scid mutation on radiation-induced transgenerational instability in mice.
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Hatch, T., Derijck, A.H.A., Black, P.D., Heijden, G.W. van der, Boer, P. de, Dubrova, Y.E., Hatch, T., Derijck, A.H.A., Black, P.D., Heijden, G.W. van der, Boer, P. de, and Dubrova, Y.E.
- Abstract
Contains fulltext : 52612.pdf (publisher's version ) (Closed access), The results of a number of recent studies show that mutation rates in the offspring of irradiated parents are substantially elevated, however, the effect of parental genotype on transgenerational instability remains poorly understood. Here, we have analysed the mutation frequency at an expanded simple tandem repeat (ESTR) locus in the germline and bone marrow of the first-generation male offspring of control and irradiated male mice. The frequency of ESTR mutation was studied in the offspring of two reciprocal matings male symbol scid x female symbol BALB/c and male symbol BALB/c x female symbol scid, which were compared with that in BALB/c mice. In the offspring of the BALB/c x BALB/c and male symbol scid x female symbol BALB/c matings, which were conceived after paternal sperm irradiation, the frequency of ESTR mutation was significantly elevated in both tissues. In contrast, ESTR mutation frequency was only slightly elevated in the offspring of male symbol BALB/c x female symbol scid mating conceived after paternal irradiation. The results of this study suggest that the oocytes of scid females are unable to fully support the repair of double-strand breaks induced in paternal sperm which may in turn result in the elimination of cells/embryos containing high levels of DNA damage, thus partially preventing the manifestation of genomic instability.
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- 2007
19. Aanvullend verzekeren, ja of nee? : een onderzoek naar motieven van patiënten
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Bronkhorst, E.M., Heijden, G.W. van der, and Truin, G.J.
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Simulation studies of the Dutch dental health care system ,Simulatiestudies van de tandheelkundige gezondheidszorg ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) - Abstract
Contains fulltext : 25947.PDF (Publisher’s version ) (Open Access)
- Published
- 1997
20. Fen1 does not control somatic hypermutability of the (CTG)(n)*(CAG)(n) repeat in a knock-in mouse model for DM1.
- Author
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Broek, W.J.A.A. van den, Nelen, M.R., Heijden, G.W. van der, Wansink, D.G., Wieringa, B., Broek, W.J.A.A. van den, Nelen, M.R., Heijden, G.W. van der, Wansink, D.G., and Wieringa, B.
- Abstract
Contains fulltext : 49344.pdf (publisher's version ) (Closed access), The mechanism of trinucleotide repeat expansion, an important cause of neuromuscular and neurodegenerative diseases, is poorly understood. We report here on the study of the role of flap endonuclease 1 (Fen1), a structure-specific nuclease with both 5' flap endonuclease and 5'-3' exonuclease activity, in the somatic hypermutability of the (CTG)(n)*(CAG)(n) repeat of the DMPK gene in a mouse model for myotonic dystrophy type 1 (DM1). By intercrossing mice with Fen1 deficiency with transgenics with a DM1 (CTG)(n)*(CAG)(n) repeat (where 104n110), we demonstrate that Fen1 is not essential for faithful maintenance of this repeat in early embryonic cleavage divisions until the blastocyst stage. Additionally, we found that the frequency of somatic DM1 (CTG)(n)*(CAG)(n) repeat instability was essentially unaltered in mice with Fen1 haploinsufficiency up to 1.5 years of age. Based on these findings, we propose that Fen1, despite its role in DNA repair and replication, is not primarily involved in maintaining stability at the DM1 locus.
- Published
- 2006
21. gammaH2AX signalling during sperm chromatin remodelling in the mouse zygote.
- Author
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Derijck, A.H.A., Heijden, G.W. van der, Giele, M.M., Philippens, M.E.P., Bavel, C.C.A.W. van, Boer, P. de, Derijck, A.H.A., Heijden, G.W. van der, Giele, M.M., Philippens, M.E.P., Bavel, C.C.A.W. van, and Boer, P. de
- Abstract
Contains fulltext : 49280.pdf (publisher's version ) (Closed access), In the mouse, the paternal post-meiotic chromatin is assumed to be devoid of DNA repair after nuclear elongation and protamine-induced compaction. Hence, DNA lesions induced thereafter will have to be restored upon gamete fusion in the zygote. Misrepair of such lesions often results in chromosome type aberrations at the first cleavage division, suggesting that the repair event takes place prior to S-phase. During this stage of the zygotic cell cycle, the paternal chromatin transits from a protamine- to a nucleosome-based state. We addressed the question whether the canonical signalling pathway to DNA double strand breaks (DSBs), the phosphorylated form of histone H2AX (gammaH2AX) is active during chromatin restructuring of the male genetic complement in the zygote. Here, we describe the detailed characterization of gammaH2AX signalling in the early stages of zygotic development up to the appearance of the pronuclei. We have found the gammaH2AX signalling pathway to be already active during sperm chromatin remodelling after gamete fusion in a dose dependent manner, reflecting the amount of DSBs present in the sperm nucleus after in vivo male irradiation. Using DNA damaging compounds to induce lesions in the early zygote, differences in DSB sensitivity and gammaH2AX processing between paternal and maternal chromatin were found, suggesting differences in DNA repair capacity between the parental chromatin sets.
- Published
- 2006
22. Asymmetry in histone H3 variants and lysine methylation between paternal and maternal chromatin of the early mouse zygote.
- Author
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Heijden, G.W. van der, Dieker, J.W.C., Derijck, A.H.A., Muller, S., Berden, J.H.M., Braat, D.D.M., Vlag, J. van der, Boer, P. de, Heijden, G.W. van der, Dieker, J.W.C., Derijck, A.H.A., Muller, S., Berden, J.H.M., Braat, D.D.M., Vlag, J. van der, and Boer, P. de
- Abstract
Contains fulltext : 33250.pdf (publisher's version ) (Closed access), In mammalian fertilization, the paternal genome is delivered to the secondary oocyte by sperm with protamine compacted DNA, while the maternal genome is arrested in meiotic metaphase II. Thus, at the beginning of fertilization, the two gametic chromatin sets are strikingly different. We elaborate on this contrast by reporting asymmetry for histone H3 type in the pre-S-phase zygote when male chromatin is virtually devoid of histone H3.1/3.2. Localization of the histone H3.3/H4 assembly factor Hira with the paternal chromatin indicates the presence of histone H3.3. In conjunction with this, we performed a systematic immunofluorescence analysis of histone N-tail methylations at position H3K4, H3K9, H3K27 and H4K20 up to the young pronucleus stage and show that asymmetries reported earlier are systematic for virtually all di- and tri-methylations but not for mono-methylation of H3K4 and H4K20, the only marks studied present in the early male pronucleus. For H4K20 the expanding male chromatin is rapidly mono-methylated. This coincides with the formation of maternally derived nucleosomes, a process which is observed as early as sperm chromatin decondensation occurs. Absence of tri-methylated H3K9, tri-methylated H4K20 and presence of loosely anchored HP1-beta combined with the homogenous presence of mono-methylated H4K20 suggests the absence of a division of the paternal chromatin in eu- and heterochromatin. In summary the male, in contrast to female G1 chromatin, is uniform and contains predominantly histone H3.3 as histone H3 variant.
- Published
- 2005
23. Effectiveness of a graded exercise therapy program for patients with chronic shoulder complaints.
- Author
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Geraets, J.J., Goossens, M.E.J.B., Groot, I.J.M. de, Bruijn, C.P. de, Bie, R.A. de, Dinant, G.J., Heijden, G.W. van der, Heuvel, W.J.A. van den, Geraets, J.J., Goossens, M.E.J.B., Groot, I.J.M. de, Bruijn, C.P. de, Bie, R.A. de, Dinant, G.J., Heijden, G.W. van der, and Heuvel, W.J.A. van den
- Abstract
Contains fulltext : 47641.pdf (publisher's version ) (Open Access), An operant behavioural and time-contingent graded exercise therapy program was developed to improve functional ability irrespective of pain experience in patients with chronic shoulder complaints. The clinical effectiveness of graded exercise therapy compared to usual care was evaluated in a randomised clinical trial. Assessments were carried out before and after 12 weeks of treatment. Performance of daily activities was measured by two outcome measures: the main complaints instrument and the Shoulder Disability Questionnaire (SDQ). Patients were eligible for participation if they had suffered from shoulder complaints for at least three months. Patients suffering from systemic diseases, referred pain or severe biomedical or psychiatric disorders were excluded. Patients (n = 176) were randomised and allocated either to graded exercise therapy (n = 87) or usual care (n = 89). Graded exercise therapy led to greater improvement in the performance of daily activities than usual care. However, only mean differences between groups in performance of activities related to the main complaints reached statistical significance (p = 0.049; 95% CI 0.0 to 15.0). The observed beneficial effects were considered to be small to moderate (calculated effect sizes: 0.30 for the main complaints instrument and 0.07 for the SDQ). Subgroup analysis showed larger improvements on the mean complaints instrument in patients not reporting pain reduction over time. Graded exercise therapy seems to be less effective in restoring performance of daily activities as assessed by the SDQ in patients showing a painful arc during physical examination. Results showed that graded exercise therapy is more effective in restoring the ability to daily activities in patients with chronic shoulder complaints than usual care, although beneficial effects are small.
- Published
- 2005
24. Reduced oocyte activation and first cleavage rate after ICSI with spermatozoa from a sterile mouse chromosome mutant.
- Author
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Baart, E.B., Heijden, G.W. van der, Hoeven, F.A. van der, Bakker, R., Cooper, T.G., Boer, P. de, Baart, E.B., Heijden, G.W. van der, Hoeven, F.A. van der, Bakker, R., Cooper, T.G., and Boer, P. de
- Abstract
Contains fulltext : 57746.pdf (publisher's version ) (Open Access)
- Published
- 2004
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