Mol. Hum. Reprod. Advance Access originally published online on January 4, 2008
Molecular Human Reproduction 2008 14(2):67-74; doi:10.1093/molehr/gam093
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Abnormal methylation of imprinted genes in human sperm is associated with oligozoospermia
1Department of Genetics, Faculty of Medicine, Porto 4200-319, Portugal 2Centre for Reproductive Genetics Alberto Barros, Porto 4100-009, Portugal 3Lab Cell Biology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Largo Prof. Abel Salazar 2, Porto 4099-003, Portugal
7 Correspondence address. Tel: +351-22-206-22-17; Fax: +351-22-206-22-32; E-mail: msousa{at}icbas.up.pt
Genomic imprinting marks in the male germ line are already established in the adult germinal stem cell population. We studied the methylation patterns of H19 and MEST imprinted genes in sperm of control and oligozoospermic patients, by bisulphite genomic sequencing. We here report that 7 out of 15 (46.7%) patients with a sperm count below 10 x 106/ml display defective methylation of H19 and/or MEST imprinted genes. In these cases, hypomethylation was observed in 5.54% (1.2–8.3%) and complete unmethylation in 2.95% (0–5.9%) of H19 clones. Similarly, for the CTCF-binding site 6, hypomethylation occurred in 4.8% (1.2–8.9%) and complete unmethylation in 3.7% (0–6.9%) of the clones. Conversely, hypermethylation occurred in 8.3% (3.8–12.2%) and complete methylation in 6.1% (3.8–7.6%) of MEST clones. Of the seven patients presenting imprinting errors, two had both H19 hypomethylation and MEST hypermethylation, whereas five displayed only one imprinted gene affected. The frequency of patients with MEST hypermethylation was highest in the severe oligozoospermia group (2/5 patients), whereas H19 hypomethylation was more frequent in the moderate oligozoospermia (2/5 patients). In all cases, global sperm genome methylation analysis (LINE1 transposon) suggested that defects were specific for imprinted genes. These findings could contribute to an explanation of the cause of Silver–Russell syndrome in children born with H19 hypomethylation after assisted reproductive technologies (ART). Additionally, unmethylation of the CTCF-binding site could lead to inactivation of the paternal IGF2 gene, and be linked to decreased embryo quality and birth weight, often associated with ART.
Key words: genomic imprinting/male infertility/oligozoospermia/DNA methylation
Submitted on October 15, 2007; resubmitted on December 6, 2007; accepted on December 19, 2007.
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