Increased prevalence of imprinting defects in patients with Angelman syndrome born to subfertile couples

Ludwig, Michael; Katalinic, Alexander; Groß, Stephanie; Sutcliffe, Alastair; Varon, Raymonda; Horsthemke, Bernhard

doi:10.1136/jmg.2004.026930

Cited by 285 publications

(200 citation statements)

References 19 publications

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“…Previous studies have reported the presence of imprinting abnormalities or hypomethylation at imprinted genes in the sperm of unobstructed normozoospermic men used as controls (Kobayashi et al 2007, Poplinski et al 2009, Boissonnas et al 2010. However, abnormal methylation in these men may be related to subfertility (Ludwig et al 2005), as these men were not of proven fertility. Sperm DNA methylation at imprinted genes appears well conserved in unobstructed men of proven fertility status, as suggested by our data and those of Hammoud et al (2010).…”

Section: Analysis Of Methylation In Testicular Spermmentioning

confidence: 87%

Aberrant DNA methylation at imprinted genes in testicular sperm retrieved from men with obstructive azoospermia and undergoing vasectomy reversal

Minor¹,

Chow²,

Ma³

2011

Reproduction

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Male factor infertility has been associated with abnormal DNA methylation at imprinted genes. Little information is available on the status of imprinting in the sperm of men with azoospermia, including the association between aberrant imprinting and obstructive azoospermia (OA) or non-OA (NOA). Analysis of DNA methylation at imprinted genes in the sperm of men undergoing vasectomy reversal would aid determination of whether aberrant imprinting is associated with obstruction. Testicular sperm was retrieved from testicular biopsies obtained from men with azoospermia (NZ18), including OA (NZ10), NOA (NZ5), and unknown pathology (NZ3), and from men undergoing vasectomy reversal (NZ17). Sperm was also obtained from proven fertile men (NZ9). DNA methylation was investigated at multiple CpG sites within the differentially methylated regions (DMRs) of three imprinted genes, H19, IG-GTL2 and MEST, using bisulphite sequencing. Unique clones representative of single cells were analyzed. We found a significant decrease in DNA methylation at the H19 DMR in testicular sperm of azoospermic men compared with proven fertile men. The decrease was also significant between OA and proven fertile men, and between men undergoing vasectomy reversal and proven fertile men, suggesting that aberrant DNA methylation may be associated with obstruction. Changes in DNA methylation at IG-GTL2 and MEST DMRs among groups were not significant. Our data suggest that imprinting abnormalities may be associated with obstruction and may occur in response to changes in testicular environment and not only spermatogenesis failure, as previously reported. Methylation at the H19 DMR was particularly prone to modification in testicular sperm.

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Section: Analysis Of Methylation In Testicular Spermmentioning

confidence: 87%

Aberrant DNA methylation at imprinted genes in testicular sperm retrieved from men with obstructive azoospermia and undergoing vasectomy reversal

Minor¹,

Chow²,

Ma³

2011

Reproduction

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“…This warrants further investigation of embryos from heattreated fathers at later stages in development and on their imprint status. A recent study has reported aberrant imprinting in sperm from oligospermic patients (Kobayashi et al 2007) and concerns have been expressed about the potential for increased rates of rare diseases due to imprinting disorders in children born as a result of assisted reproductive technologies (Ludwig et al 2005).…”

Section: Discussionmentioning

confidence: 99%

A single, mild, transient scrotal heat stress causes DNA damage, subfertility and impairs formation of blastocysts in mice

Paul¹,

Murray²,

Spears³

et al. 2008

Reproduction

237

168

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Infertility represents a major clinical problem and 50% of cases are attributable to the male partner. Testicular function is temperature dependent, and in both man and mouse the position of the testes in the scrotum ensures that they are kept at between 2 and 8 8C below core body temperature. We used a mouse model to investigate the impact of a single, transient, mild, scrotal heat stress (38, 40 or 42 8C for 30 min) on testicular function, sperm DNA integrity and embryo survival. We detected temperature-dependent changes in testicular architecture, number of apoptotic cells and a significant reduction in testis weight 7 and 14 days after heat stress at 42 8C. We report for the first time that DNA strand breaks (g-H2AX-positive foci) were present in spermatocytes recovered from testes subjected to 40 or 42 8C. Fertility of heat-stressed males was tested 23-28 d after treatment (sperm at this time would have been spermatocytes at time of heating). Paternal heat stress at 42 8C resulted in reduced pregnancy rate, placental weight and litter size; pregnancies from the 40 8C group had increased resorptions at e14.5. Abnormalities in embryonic development were detected at e3.5 and in vitro fertilisation with sperm recovered 16 h or 23 d after scrotal stress at 42 8C revealed a block in development between the 4-cell and blastocyst stages. This study has provided evidence of temperature-dependent effects on germ cell DNA integrity and highlighted the importance of an intact paternal genome for normal embryo development. Reproduction (2008) 136 73-84

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“…Although MEST, which is normally unmethylated in sperm, was unaffected, H19 showed lower levels of methylation in the sperm DNA of the oligospermic men. The second study reported an increased incidence of imprinting defects in patients with Angelman syndrome born to subfertile couples with suggestive evidence of an interaction between subfertility and assisted reproductive technologies (Ludwig et al 2005). More research is needed in both human and animal models to examine possible epigenetic causes for infertility.…”

Section: Epigenetics Genomic Imprinting and The Germ Line: Implicatimentioning

confidence: 99%

Gamete imprinting: setting epigenetic patterns for the next generation

Trasler¹

2006

Reprod. Fertil. Dev.

120

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Abstract. The acquisition of genomic DNA methylation patterns, including those important for development, begins in the germ line. In particular, imprinted genes are differentially marked in the developing male and female germ cells to ensure parent-of-origin-specific expression in the offspring. Abnormalities in imprints are associated with perturbations in growth, placental function, neurobehavioural processes and carcinogenesis. Based, for the most part, on data from the well-characterised mouse model, the present review will describe recent studies on the timing and mechanisms underlying the acquisition and maintenance of DNA methylation patterns in gametes and early embryos, as well as the consequences of altering these patterns.

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Increased prevalence of imprinting defects in patients with Angelman syndrome born to subfertile couples

Cited by 285 publications

References 19 publications

Aberrant DNA methylation at imprinted genes in testicular sperm retrieved from men with obstructive azoospermia and undergoing vasectomy reversal

Aberrant DNA methylation at imprinted genes in testicular sperm retrieved from men with obstructive azoospermia and undergoing vasectomy reversal

A single, mild, transient scrotal heat stress causes DNA damage, subfertility and impairs formation of blastocysts in mice

Gamete imprinting: setting epigenetic patterns for the next generation

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