title: Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor.
abstract: We have analyzed several cases of Beckwith-Wiedemann syndrome (BWS) with Wilms' tumor in a familial setting, which give insight into the complex controls of imprinting and gene expression in the chromosome 11p15 region. We describe a 2.2-kbp microdeletion in the H19/insulin-like growth factor 2 (IGF2)-imprinting center eliminating three target sites of the chromatin insulator protein CTCF that we believe here is necessary, but not sufficient, to cause BWS and Wilms' tumor. Maternal inheritance of the deletion is associated with IGF2 loss of imprinting and up-regulation of IGF2 mRNA. However, in at least one affected family member a second genetic lesion (a duplication of maternal 11p15) was identified and accompanied by a further increase in IGF2 mRNA levels 35-fold higher than control values. Our results suggest that the combined effects of the H19/IGF2-imprinting center microdeletion and 11p15 chromosome duplication were necessary for manifestation of BWS.
authors.affiliation: Children's Hospital, University of Mainz, Langenbeckstrasse 1, D-55101 Mainz, Germany. prawitt@molgen.medizin.uni-mainz.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Prawitt
authors.forename: Thorsten
authors.initials: T
authors.lastname: Enklaar
authors.forename: Barbara
authors.initials: B
authors.lastname: Gärtner-Rupprecht
authors.forename: Christian
authors.initials: C
authors.lastname: Spangenberg
authors.forename: Monika
authors.initials: M
authors.lastname: Oswald
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Peter
authors.initials: P
authors.lastname: Schmidtke
authors.forename: Dirk
authors.initials: D
authors.lastname: Reutzel
authors.forename: Stephan
authors.initials: S
authors.lastname: Fees
authors.forename: Rob
authors.initials: R
authors.lastname: Lucito
authors.forename: Maria
authors.initials: M
authors.lastname: Korzon
authors.forename: Izabela
authors.initials: I
authors.lastname: Brozek
authors.forename: Janusz
authors.initials: J
authors.lastname: Limon
authors.forename: David E
authors.initials: DE
authors.lastname: Housman
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
mesh_terms: D001483:Base Sequence; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D000076246:CCCTC-Binding Factor; D002880:Chromosomes, Human, Pair 11; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008297:Male; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics*; D017384:Sequence Deletion; D009396:Wilms Tumor / Q000235:genetics*
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D007335:Insulin-Like Growth Factor II
references.citation: Cancer Res. 2002 Nov 15;62(22):6442-6
references.pmid: 12438232
references.citation: J Mol Biol. 2003 Jan 31;325(5):873-87
references.pmid: 12527297
references.citation: Hum Mol Genet. 2003 Mar 1;12(5):535-49
references.pmid: 12588801
references.citation: Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R61-8
references.pmid: 12668598
references.citation: Cancer Res. 2003 Apr 15;63(8):1900-5
references.pmid: 12702581
references.citation: Science. 2004 Jan 9;303(5655):238-40
references.pmid: 14716017
references.citation: Oncogene. 2004 May 27;23(25):4380-8
references.pmid: 15007390
references.citation: Nat Genet. 2004 Sep;36(9):958-60
references.pmid: 15314640
references.citation: Am J Hum Genet. 2004 Nov;75(5):844-9
references.pmid: 15372379
references.citation: Cytogenet Cell Genet. 1992;59(4):311-2
references.pmid: 1544332
references.citation: Nature. 1993 Apr 22;362(6422):747-9
references.pmid: 8385745
references.citation: Development. 1995 Feb;121(2):309-16
references.pmid: 7768174
references.citation: Hum Mol Genet. 1995 Dec;4(12):2379-85
references.pmid: 8634713
references.citation: J Endocrinol. 1996 Jun;149(3):367-72
references.pmid: 8691094
references.citation: Cytogenet Cell Genet. 1996;75(2-3):132-5
references.pmid: 9040778
references.citation: Nature. 1997 Oct 23;389(6653):809-15
references.pmid: 9349812
references.citation: Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8064-9
references.pmid: 10393948
references.citation: J Biol Chem. 1999 Oct 8;274(41):29331-40
references.pmid: 10506193
references.citation: Genes Dev. 1999 Dec 1;13(23):3115-24
references.pmid: 10601037
references.citation: Nature. 2000 May 25;405(6785):482-5
references.pmid: 10839546
references.citation: Nature. 2000 May 25;405(6785):486-9
references.pmid: 10839547
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):591-6
references.pmid: 11120891
references.citation: Mol Biol Rep. 2000 Sep;27(3):157-65
references.pmid: 11254105
references.citation: Biochem Biophys Res Commun. 2001 May 25;283(5):1124-30
references.pmid: 11355889
references.citation: Cancer Res. 2001 Jul 1;61(13):4947-50
references.pmid: 11431321
references.citation: Annu Rev Genomics Hum Genet. 2001;2:153-75
references.pmid: 11701647
references.citation: Hum Mol Genet. 2001 Nov 1;10(23):2619-26
references.pmid: 11726548
references.citation: Mol Cell Biol. 2002 May;22(10):3339-44
references.pmid: 11971967
references.citation: J Biol Chem. 2002 Aug 2;277(31):27960-7
references.pmid: 12029086
references.citation: Oncogene. 2002 Aug 22;21(37):5684-95
references.pmid: 12173038
references.citation: Hum Genet. 2002 Sep;111(3):290-6
references.pmid: 12215843