Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor.
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.
Prawitt
Dirk
D
Children's Hospital, University of Mainz, Langenbeckstrasse 1, D-55101 Mainz, Germany. prawitt@molgen.medizin.uni-mainz.de
Enklaar
Thorsten
T
Gärtner-Rupprecht
Barbara
B
Spangenberg
Christian
C
Oswald
Monika
M
Lausch
Ekkehart
E
Schmidtke
Peter
P
Reutzel
Dirk
D
Fees
Stephan
S
Lucito
Rob
R
Korzon
Maria
M
Brozek
Izabela
I
Limon
Janusz
J
Housman
David E
DE
Pelletier
Jerry
J
Zabel
Bernhard
B
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*
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D007335:Insulin-Like Growth Factor II
Cancer Res. 2002 Nov 15;62(22):6442-6
12438232
J Mol Biol. 2003 Jan 31;325(5):873-87
12527297
Hum Mol Genet. 2003 Mar 1;12(5):535-49
12588801
Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R61-8
12668598
Cancer Res. 2003 Apr 15;63(8):1900-5
12702581
Science. 2004 Jan 9;303(5655):238-40
14716017
Oncogene. 2004 May 27;23(25):4380-8
15007390
Nat Genet. 2004 Sep;36(9):958-60
15314640
Am J Hum Genet. 2004 Nov;75(5):844-9
15372379
Cytogenet Cell Genet. 1992;59(4):311-2
1544332
Nature. 1993 Apr 22;362(6422):747-9
8385745
Development. 1995 Feb;121(2):309-16
7768174
Hum Mol Genet. 1995 Dec;4(12):2379-85
8634713
J Endocrinol. 1996 Jun;149(3):367-72
8691094
Cytogenet Cell Genet. 1996;75(2-3):132-5
9040778
Nature. 1997 Oct 23;389(6653):809-15
9349812
Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8064-9
10393948
J Biol Chem. 1999 Oct 8;274(41):29331-40
10506193
Genes Dev. 1999 Dec 1;13(23):3115-24
10601037
Nature. 2000 May 25;405(6785):482-5
10839546
Nature. 2000 May 25;405(6785):486-9
10839547
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):591-6
11120891
Mol Biol Rep. 2000 Sep;27(3):157-65
11254105
Biochem Biophys Res Commun. 2001 May 25;283(5):1124-30
11355889
Cancer Res. 2001 Jul 1;61(13):4947-50
11431321
Annu Rev Genomics Hum Genet. 2001;2:153-75
11701647
Hum Mol Genet. 2001 Nov 1;10(23):2619-26
11726548
Mol Cell Biol. 2002 May;22(10):3339-44
11971967
J Biol Chem. 2002 Aug 2;277(31):27960-7
12029086
Oncogene. 2002 Aug 22;21(37):5684-95
12173038
Hum Genet. 2002 Sep;111(3):290-6
12215843