{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:30:15Z","timestamp":1791412215703,"version":"4.3.3"},"reference-count":44,"publisher":"The Company of Biologists","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,3,15]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1242\/dev.02293","type":"journal-article","created":{"date-parts":[[2006,2,24]],"date-time":"2006-02-24T22:44:07Z","timestamp":1140821047000},"page":"1183-1192","source":"Crossref","is-referenced-by-count":159,"title":["Roles for Dnmt3b in mammalian development: a mouse model for the ICF syndrome"],"prefix":"10.1242","volume":"133","author":[{"given":"Yoshihide","family":"Ueda","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Okano","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA."},{"name":"Center for Developmental Biology, RIKEN, Kobe Hyogo 650-0047, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Williams","sequence":"additional","affiliation":[{"name":"Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiping","family":"Chen","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA."},{"name":"Epigenetics Program, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Georgopoulos","sequence":"additional","affiliation":[{"name":"Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"En","family":"Li","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA."},{"name":"Epigenetics Program, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042605435958900_REF1","doi-asserted-by":"crossref","unstructured":"Bachman, K. E., Rountree, M. R. and Baylin, S. B.(2001). Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. J. Biol. Chem.276,32282-32287.","DOI":"10.1074\/jbc.M104661200"},{"key":"2021042605435958900_REF2","doi-asserted-by":"crossref","unstructured":"Brown, D. C., Grace, E., Sumner, A. T., Edmunds, A. T. and Ellis, P. M. (1995). ICF syndrome (immunodeficiency,centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome. Hum. Genet.96,411-416.","DOI":"10.1007\/BF00191798"},{"key":"2021042605435958900_REF3","doi-asserted-by":"crossref","unstructured":"Bruniquel, D. and Schwartz, R. H. (2003). Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat. Immunol.4, 235-240.","DOI":"10.1038\/ni887"},{"key":"2021042605435958900_REF4","doi-asserted-by":"crossref","unstructured":"Carpenter, N. J., Filipovich, A., Blaese, R. M., Carey, T. L. and Berkel, A. I. (1988). Variable immunodeficiency with abnormal condensation of the heterochromatin of chromosomes 1, 9, and 16. J. Pediatr.112,757-760.","DOI":"10.1016\/S0022-3476(88)80698-X"},{"key":"2021042605435958900_REF5","doi-asserted-by":"crossref","unstructured":"Chen, T., Ueda, Y., Xie, S. and Li, E. (2002). A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation. J. Biol. Chem.277,38746-38754.","DOI":"10.1074\/jbc.M205312200"},{"key":"2021042605435958900_REF6","doi-asserted-by":"crossref","unstructured":"Chen, T., Ueda, Y., Dodge, J. E., Wang, Z. and Li, E.(2003). Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol. Cell. Biol.23,5594-5605.","DOI":"10.1128\/MCB.23.16.5594-5605.2003"},{"key":"2021042605435958900_REF7","doi-asserted-by":"crossref","unstructured":"Chen, T., Tsujimoto, N. and Li, E. (2004). The PWWP domain of Dnmt3a and Dnmt3b is required for directing DNA methylation to the major satellite repeats at pericentric heterochromatin. Mol. Cell. Biol.24,9048-9058.","DOI":"10.1128\/MCB.24.20.9048-9058.2004"},{"key":"2021042605435958900_REF8","doi-asserted-by":"crossref","unstructured":"Dennis, K., Fan, T., Geiman, T., Yan, Q. and Muegge, K.(2001). Lsh, a member of the SNF2 family, is required for genome-wide methylation. Genes Dev.15,2940-2944.","DOI":"10.1101\/gad.929101"},{"key":"2021042605435958900_REF9","doi-asserted-by":"crossref","unstructured":"Dodge, J. E., Okano, M., Dick, F., Tsujimoto, N., Chen, T.,Wang, S., Ueda, Y., Dyson, N. and Li, E. (2005). Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation,chromosomal instability, and spontaneous immortalization. J. Biol. Chem.280,17986-17991.","DOI":"10.1074\/jbc.M413246200"},{"key":"2021042605435958900_REF10","doi-asserted-by":"crossref","unstructured":"Ehrlich, M. (2003). The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. Clin. Immunol.109,17-28.","DOI":"10.1016\/S1521-6616(03)00201-8"},{"key":"2021042605435958900_REF11","doi-asserted-by":"crossref","unstructured":"Fan, G., Beard, C., Chen, R. Z., Csankovszki, G., Sun, Y.,Siniaia, M., Biniszkiewicz, D., Bates, B., Lee, P. P., Kuhn, R. et al.(2001). DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J. Neurosci.21,788-797.","DOI":"10.1523\/JNEUROSCI.21-03-00788.2001"},{"key":"2021042605435958900_REF12","doi-asserted-by":"crossref","unstructured":"Fasth, A., Forestier, E., Holmberg, E., Holmgren, G., Nordenson,I., Soderstrom, T. and Wahlstrom, J. (1990). Fragility of the centromeric region of chromosome 1 associated with combined immunodeficiency in siblings. A recessively inherited entity? Acta Paediatr. Scand.79,605-612.","DOI":"10.1111\/j.1651-2227.1990.tb11524.x"},{"key":"2021042605435958900_REF13","doi-asserted-by":"crossref","unstructured":"Fitzpatrick, D. R., Shirley, K. M., McDonald, L. E.,Bielefeldt-Ohmann, H., Kay, G. F. and Kelso, A. (1998). Distinct methylation of the interferon gamma (IFN-gamma) and interleukin 3(IL-3) genes in newly activated primary CD8+ T lymphocytes: regional IFN-gamma promoter demethylation and mRNA expression are heritable in CD44 (high) CD8+ T cells. J. Exp. Med.188,103-117.","DOI":"10.1084\/jem.188.1.103"},{"key":"2021042605435958900_REF14","doi-asserted-by":"crossref","unstructured":"Gaudet, F., Hodgson, J. G., Eden, A., Jackson-Grusby, L.,Dausman, J., Gray, J. W., Leonhardt, H. and Jaenisch, R.(2003). Induction of tumors in mice by genomic hypomethylation. Science300,489-492.","DOI":"10.1126\/science.1083558"},{"key":"2021042605435958900_REF15","doi-asserted-by":"crossref","unstructured":"Geiman, T. M. and Muegge, K. (2000). Lsh, an SNF2\/helicase family member, is required for proliferation of mature T lymphocytes. Proc. Natl. Acad. Sci. USA97,4772-4777.","DOI":"10.1073\/pnas.97.9.4772"},{"key":"2021042605435958900_REF16","doi-asserted-by":"crossref","unstructured":"Geiman, T. M., Tessarollo, L., Anver, M. R., Kopp, J. B., Ward,J. M. and Muegge, K. (2001). Lsh, a SNF2 family member, is required for normal murine development. Biochim. Biophys. Acta1526,211-220.","DOI":"10.1016\/S0304-4165(01)00129-5"},{"key":"2021042605435958900_REF17","doi-asserted-by":"crossref","unstructured":"Georgopoulos, K., Bigby, M., Wang, J. H., Molnar, A., Wu, P.,Winandy, S. and Sharpe, A. (1994). The Ikaros gene is required for the development of all lymphoid lineages. Cell79,143-156.","DOI":"10.1016\/0092-8674(94)90407-3"},{"key":"2021042605435958900_REF18","doi-asserted-by":"crossref","unstructured":"Gowher, H. and Jeltsch, A. (2002). Molecular enzymology of the catalytic domains of the Dnmt3a and Dnmt3b DNA methyltransferases. J. Biol. Chem.277,20409-20414.","DOI":"10.1074\/jbc.M202148200"},{"key":"2021042605435958900_REF19","doi-asserted-by":"crossref","unstructured":"Hansen, R. S., Wijmenga, C., Luo, P., Stanek, A. M., Canfield,T. K., Weemaes, C. M. and Gartler, S. M. (1999). The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl. Acad. Sci. USA96,14412-14417.","DOI":"10.1073\/pnas.96.25.14412"},{"key":"2021042605435958900_REF20","doi-asserted-by":"crossref","unstructured":"Hata, K., Okano, M., Lei, H. and Li, E. (2002). Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development129,1983-1993.","DOI":"10.1242\/dev.129.8.1983"},{"key":"2021042605435958900_REF21","doi-asserted-by":"crossref","unstructured":"Hulten, M. (1978). Selective somatic pairing and fragility at 1q12 in a boy with common variable immunodeficiency. Clin. Genet.14,294.","DOI":"10.1111\/j.1399-0004.1978.tb02170.x"},{"key":"2021042605435958900_REF22","doi-asserted-by":"crossref","unstructured":"Jeanpierre, M., Turleau, C., Aurias, A., Prieur, M., Ledeist,F., Fischer, A. and Viegas-Pequignot, E. (1993). An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. Hum. Mol. Genet.2, 731-735.","DOI":"10.1093\/hmg\/2.6.731"},{"key":"2021042605435958900_REF23","doi-asserted-by":"crossref","unstructured":"Kaneda, M., Okano, M., Hata, K., Sado, T., Tsujimoto, N., Li, E. and Sasaki, H. (2004). Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature429,900-903.","DOI":"10.1038\/nature02633"},{"key":"2021042605435958900_REF24","doi-asserted-by":"crossref","unstructured":"Kim, G. D., Ni, J., Kelesoglu, N., Roberts, R. J. and Pradhan,S. (2002). Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. EMBO J.21,4183-4195.","DOI":"10.1093\/emboj\/cdf401"},{"key":"2021042605435958900_REF25","doi-asserted-by":"crossref","unstructured":"Kondo, T., Bobek, M. P., Kuick, R., Lamb, B., Zhu, X., Narayan,A., Bourc'his, D., Viegas-Pequignot, E., Ehrlich, M. and Hanash, S. M.(2000). Whole-genome methylation scan in ICF syndrome:hypomethylation of non-satellite DNA repeats D4Z4 and NBL2. Hum. Mol. Genet.9,597-604.","DOI":"10.1093\/hmg\/9.4.597"},{"key":"2021042605435958900_REF26","doi-asserted-by":"crossref","unstructured":"Lakso, M., Pichel, J. G., Gorman, J. R., Sauer, B., Okamoto, Y.,Lee, E., Alt, F. W. and Westphal, H. (1996). Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc. Natl. Acad. Sci. USA93,5860-5865.","DOI":"10.1073\/pnas.93.12.5860"},{"key":"2021042605435958900_REF27","doi-asserted-by":"crossref","unstructured":"Lee, P. P., Fitzpatrick, D. R., Beard, C., Jessup, H. K., Lehar,S., Makar, K. W., Perez-Melgosa, M., Sweetser, M. T., Schlissel, M. S.,Nguyen, S. et al. (2001). A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity15,763-774.","DOI":"10.1016\/S1074-7613(01)00227-8"},{"key":"2021042605435958900_REF28","doi-asserted-by":"crossref","unstructured":"Lei, H., Oh, S. P., Okano, M., Juttermann, R., Goss, K. A.,Jaenisch, R. and Li, E. (1996). De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development122,3195-3205.","DOI":"10.1242\/dev.122.10.3195"},{"key":"2021042605435958900_REF29","doi-asserted-by":"crossref","unstructured":"Li, E., Bestor, T. H. and Jaenisch, R. (1992). Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell69,915-926.","DOI":"10.1016\/0092-8674(92)90611-F"},{"key":"2021042605435958900_REF30","doi-asserted-by":"crossref","unstructured":"Makar, K. W., Perez-Melgosa, M., Shnyreva, M., Weaver, W. M.,Fitzpatrick, D. R. and Wilson, C. B. (2003). Active recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells. Nat. Immunol.4,1183-1190.","DOI":"10.1038\/ni1004"},{"key":"2021042605435958900_REF31","doi-asserted-by":"crossref","unstructured":"Maraschio, P., Zuffardi, O., Dalla Fior, T. and Tiepolo, L.(1988). Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies: the ICF syndrome. J. Med. Genet.25,173-180.","DOI":"10.1136\/jmg.25.3.173"},{"key":"2021042605435958900_REF32","doi-asserted-by":"crossref","unstructured":"Okano, M., Xie, S. and Li, E. (1998). Cloning and characterization of a family of novel mammalian DNA (cytosine-5)methyltransferases. Nat. Genet.19,219-220.","DOI":"10.1038\/890"},{"key":"2021042605435958900_REF33","doi-asserted-by":"crossref","unstructured":"Okano, M., Bell, D. W., Haber, D. A. and Li, E.(1999). DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell99,247-257.","DOI":"10.1016\/S0092-8674(00)81656-6"},{"key":"2021042605435958900_REF34","doi-asserted-by":"crossref","unstructured":"Shirohzu, H., Kubota, T., Kumazawa, A., Sado, T., Chijiwa, T.,Inagaki, K., Suetake, I., Tajima, S., Wakui, K., Miki, Y. et al.(2002). Three novel DNMT3B mutations in Japanese patients with ICF syndrome. Am. J. Med. Genet.112, 31-37.","DOI":"10.1002\/ajmg.10658"},{"key":"2021042605435958900_REF35","doi-asserted-by":"crossref","unstructured":"Smeets, D. F., Moog, U., Weemaes, C. M., Vaes-Peeters, G.,Merkx, G. F., Niehof, J. P. and Hamers, G. (1994). ICF syndrome: a new case and review of the literature. Hum. Genet.94,240-246.","DOI":"10.1007\/BF00208277"},{"key":"2021042605435958900_REF36","doi-asserted-by":"crossref","unstructured":"Tiepolo, L., Maraschio, P., Gimelli, G., Cuoco, C., Gargani, G. F. and Romano, C. (1979). Multibranched chromosomes 1, 9, and 16 in a patient with combined IgA and IgE deficiency. Hum. Genet.51,127-137.","DOI":"10.1007\/BF00287166"},{"key":"2021042605435958900_REF37","doi-asserted-by":"crossref","unstructured":"Turleau, C., Cabanis, M. O., Girault, D., Ledeist, F., Mettey,R., Puissant, H., Prieur, M. and de Grouchy, J. (1989). Multibranched chromosomes in the ICF syndrome: immunodeficiency, centromeric instability, and facial anomalies. Am. J. Med. Genet.32,420-424.","DOI":"10.1002\/ajmg.1320320331"},{"key":"2021042605435958900_REF38","doi-asserted-by":"crossref","unstructured":"Webb, S., Brown, N. A. and Anderson, R. H.(1998). Formation of the atrioventricular septal structures in the normal mouse. Circ. Res.82,645-656.","DOI":"10.1161\/01.RES.82.6.645"},{"key":"2021042605435958900_REF39","doi-asserted-by":"crossref","unstructured":"Wijmenga, C., Hansen, R. S., Gimelli, G., Bjorck, E. J., Davies,E. G., Valentine, D., Belohradsky, B. H., van Dongen, J. J., Smeets, D. F.,van den Heuvel, L. P. et al. (2000). Genetic variation in ICF syndrome: evidence for genetic heterogeneity. Hum. Mutat.16,509-517.","DOI":"10.1002\/1098-1004(200012)16:6<509::AID-HUMU8>3.0.CO;2-V"},{"key":"2021042605435958900_REF40","doi-asserted-by":"crossref","unstructured":"Winandy, S., Wu, P. and Georgopoulos, K.(1995). A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell83,289-299.","DOI":"10.1016\/0092-8674(95)90170-1"},{"key":"2021042605435958900_REF41","doi-asserted-by":"crossref","unstructured":"Xie, S., Wang, Z., Okano, M., Nogami, M., Li, Y., He, W. W.,Okumura, K. and Li, E. (1999). Cloning, expression and chromosome locations of the human DNMT3 gene family. Gene236,87-95.","DOI":"10.1016\/S0378-1119(99)00252-8"},{"key":"2021042605435958900_REF42","doi-asserted-by":"crossref","unstructured":"Xu, G. L., Bestor, T. H., Bourc'his, D., Hsieh, C. L., Tommerup,N., Bugge, M., Hulten, M., Qu, X., Russo, J. J. and Viegas-Pequignot, E.(1999). Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature402,187-191.","DOI":"10.1038\/46052"},{"key":"2021042605435958900_REF43","doi-asserted-by":"crossref","unstructured":"Yan, Q., Cho, E., Lockett, S. and Muegge, K.(2003a). Association of Lsh, a regulator of DNA methylation, with pericentromeric heterochromatin is dependent on intact heterochromatin. Mol. Cell. Biol.23,8416-8428.","DOI":"10.1128\/MCB.23.23.8416-8428.2003"},{"key":"2021042605435958900_REF44","doi-asserted-by":"crossref","unstructured":"Yan, Q., Huang, J., Fan, T., Zhu, H. and Muegge, K.(2003b). Lsh, a modulator of CpG methylation, is crucial for normal histone methylation. EMBO J.22,5154-5162.","DOI":"10.1093\/emboj\/cdg493"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/133\/6\/1183\/1518398\/1183.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/133\/6\/1183\/1518398\/1183.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T03:21:45Z","timestamp":1706930505000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/133\/6\/1183\/43533\/Roles-for-Dnmt3b-in-mammalian-development-a-mouse"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,3,15]]},"references-count":44,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2006,3,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.02293","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2006,3,15]]}}}