title: Roles for Dnmt3b in mammalian development: a mouse model for the ICF syndrome.
abstract: ICF (Immunodeficiency, Centromeric instability and Facial anomalies) syndrome is a rare autosomal recessive disease caused by mutations in the DNA methyltransferase gene DNMT3B. To investigate the function of Dnmt3b in mouse development and to create animal models for ICF syndrome, we have generated three mutant alleles of Dnmt3b in mice: one carrying a deletion of the catalytic domain (null allele) and two carrying ICF-like missense mutations in the catalytic domain. The Dnmt3b null allele results in embryonic lethality from E14.5 to E16.5 with multiple tissue defects, including liver hypotrophy, ventricular septal defect and haemorrhage. By contrast, mice homozygous for the ICF mutations develop to term and some survive to adulthood. These mice show phenotypes that are reminiscent of ICF patients, including hypomethylation of repetitive sequences, low body weight, distinct cranial facial anomalies and T cell death by apoptosis. These results indicate that Dnmt3b plays an essential role at different stages of mouse development, and that ICF missense mutations cause partial loss of function. These mutant mice will be useful for further elucidation of the pathogenic and molecular mechanisms underlying ICF syndrome.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Ueda
authors.forename: Masaki
authors.initials: M
authors.lastname: Okano
authors.forename: Christine
authors.initials: C
authors.lastname: Williams
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
authors.forename: Katia
authors.initials: K
authors.lastname: Georgopoulos
authors.forename: En
authors.initials: E
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002503:Centromere / Q000235:genetics* / Q000473:pathology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D005145:Face / Q000002:abnormalities*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000196:embryology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D013577:Syndrome; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000097584:DNA Methyltransferase 3B