DNA methylation errors at imprinted loci after assisted conception originate in the parental sperm

• Published in: European journal of human genetics : EJHG Vol. 17; no. 12; pp. 1582 - 1591
• Main Authors: KOBAYASHI, Hisato, HIURA, Hitoshi, YAEGASHI, Nobuo, ARIMA, Takahiro, JOHN, Rosalind M, SATO, Akiko, OTSU, Eiko, KOBAYASHI, Naoko, SUZUKI, Rei, SUZUKI, Fumihiko, HAYASHI, Chika, UTSUNOMIYA, Takafumi
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.12.2009
• Subjects: Animal models; Beckwith-Wiedemann syndrome; Biological and medical sciences; Biomedical engineering; Classical genetics, quantitative genetics, hybrids; Congenital diseases; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA methylation; DNA Methylation - genetics; DNA Mutational Analysis; Embryo, Mammalian - metabolism; Embryos; Enzymes; Epigenetics; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetic Loci - genetics; Genetic testing; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomic Imprinting - genetics; Gynecology. Andrology. Obstetrics; Human; Humans; Imprinting; In vitro fertilization; Infertility, Male - enzymology; Infertility, Male - genetics; Male; Male and female genital diseases. Gonadal dysgenesis. Hermaphroditism. Sex hormones resistance; Medical genetics; Medical sciences; Methylation; Molecular and cellular biology; Mutation; Mutation - genetics; Nucleotide sequence; Parents; Polymerase Chain Reaction; Pregnancy; Proteins; Reproduction; Reproductive Techniques, Assisted; Reproductive technologies; Sperm; Spermatozoa - enzymology; Spermatozoa - metabolism; University graduates; United States > US; Japan; Human; oligospermic patients; Enzyme; Semen; Transferases; Error; Patient; Semen disorders; Protein; Genomic imprinting; Oligospermia; DNA methyltransferase 3-like protein; Methyltransferases; DNA; DNA methylation; Genetics; Locus; Methylation; Male genital diseases; assisted reproductive technologies
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2009.68

There is an increased prevalence of imprinting disorders, such as Beckwith-Wiedemann syndrome, associated with human assisted reproductive technologies (ART). Work on animal models suggests that in vitro culture may be the source of these imprinting errors. However, in this study we report that, in some cases, the errors are inherited from the father. We analyzed DNA methylation at seven autosomal imprinted loci and the XIST locus in 78 paired DNA samples. In seven out of seventeen cases where there was abnormal DNA methylation in the ART sample (41%), the identical alterations were present in the parental sperm. Furthermore, we also identified DNA sequence variations in the gene encoding DNMT3L, which were associated with the abnormal paternal DNA methylation. Both the imprinting errors and the DNA sequence variants were more prevalent in patients with oligospermia. Our data suggest that the increase in the incidence of imprinting disorders in individuals born by ART may be due, in some cases, to the use of sperm with intrinsic imprinting mutations.