title: DNA methylation errors at imprinted loci after assisted conception originate in the parental sperm.
abstract: 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.
authors.affiliation: Innovation of New Biomedical Engineering Center, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hiura
authors.forename: Rosalind M
authors.initials: RM
authors.lastname: John
authors.forename: Akiko
authors.initials: A
authors.lastname: Sato
authors.forename: Eiko
authors.initials: E
authors.lastname: Otsu
authors.forename: Naoko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Rei
authors.initials: R
authors.lastname: Suzuki
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Suzuki
authors.forename: Chika
authors.initials: C
authors.lastname: Hayashi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Utsunomiya
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yaegashi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Arima
mesh_terms: D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D004622:Embryo, Mammalian / Q000378:metabolism; D056426:Genetic Loci / Q000235:genetics*; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007248:Infertility, Male / Q000201:enzymology / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D010290:Parents; D016133:Polymerase Chain Reaction; D027724:Reproductive Techniques, Assisted; D013094:Spermatozoa / Q000201:enzymology / Q000378:metabolism*
chemical_list: C000717967:DNMT3A protein, human; C412484:DNMT3L protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A