title: Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2.
abstract: Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections. About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1). The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences. We performed homozygosity mapping in five unrelated ICF2 patients with consanguineous parents and then performed whole-exome sequencing in one of these patients and Sanger sequencing in all to identify mutations in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24) gene in four consanguineously descended ICF2 patients. Additionally, we found ZBTB24 mutations in an affected sibling pair and in one patient for whom it was not known whether his parents were consanguineous. ZBTB24 belongs to a large family of transcriptional repressors that include members, such as BCL6 and PATZ1, with prominent regulatory roles in hematopoietic development and malignancy. These data thus indicate that ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions. Because ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage, we predict that by studying the molecular function of ZBTB24, we will improve our understanding of the molecular pathophysiology of ICF syndrome and of lymphocyte biology in general.
authors: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Jessica C
authors: JC
authors: de Greef
authors: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Jun
authors: J
authors: Wang
authors: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Judit
authors: J
authors: Balog
authors: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Johan T
authors: JT
authors: den Dunnen
authors: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Rune R
authors: RR
authors: Frants
authors: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Kirsten R
authors: KR
authors: Straasheijm
authors: Department of Pediatric Immunology, Dr. Sami Ulus Children's Health and Diseases Training and Research Center, 06080 Ankara, Turkey.
authors: Caner
authors: C
authors: Aytekin
authors: Department of Immunology, Erasmus Medical Center, University Medical Center Rotterdam, 3015 CE Rotterdam, The Netherlands.
authors: Mirjam
authors: M
authors: van der Burg
authors: Department of Medical Genetics, Hôpital Erasme-Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors: Laurence
authors: L
authors: Duprez
authors: Department of Paediatrics, Haemato-Oncology Unit, Hôpital Universitaire des Enfants Reine Fabiola- Université Libre de Bruxelles, 1020 Brussels, Belgium.
authors: Alina
authors: A
authors: Ferster
authors: Department of Paediatric Immunology, Newcastle Upon Tyne Hospital, NHS Foundation Trust, Newcastle Upon Tyne, UK and Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE7 7DN, UK.
authors: Andrew R
authors: AR
authors: Gennery
authors: Laboratorio di Citogenetica, Instituto Giannina Gaslini, 16148 Genoa, Italy.
authors: Giorgio
authors: G
authors: Gimelli
authors: Department of Pediatric Immunology and Allergy, Selcuk University, 42003 Konya, Turkey.
authors: Ismail
authors: I
authors: Reisli
authors: Department of Pediatrics and Adolescent Medicine, University Hospital Ulm, 89075 Ulm, Germany.
authors: Catharina
authors: C
authors: Schuetz
authors: Department of Pediatrics and Adolescent Medicine, University Hospital Ulm, 89075 Ulm, Germany.
authors: Ansgar
authors: A
authors: Schulz
authors: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6526 GA Nijmegen, The Netherlands.
authors: Dominique F C M
authors: DFCM
authors: Smeets
authors: Pediatric Clinical Genetics and Center for Human Genetics, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), 1020 Brussels, Belgium.
authors: Yves
authors: Y
authors: Sznajer
authors: Genetics Department, University Medical Center and Groningen University, 9713 GZ Groningen, The Netherlands.
authors: Cisca
authors: C
authors: Wijmenga
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Marja C
authors: MC
authors: van Eggermond
authors: Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Monique M
authors: MM
authors: van Ostaijen-Ten Dam
authors: Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Arjan C
authors: AC
authors: Lankester
authors: Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Maarten J D
authors: MJD
authors: van Tol
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Pathology, Vrije Universiteit University Medical Center, 1081 HV Amsterdam, The Netherlands.
authors: Peter J
authors: PJ
authors: van den Elsen
authors: Department of Paediatric Infectious Diseases and Immunology, Radboud University Nijmegen Medical Centre, 6526 GA Nijmegen, The Netherlands.
authors: Corry M
authors: CM
authors: Weemaes
authors: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. Electronic address: maarel@lumc.nl.
authors: Silvère M
authors: SM
authors: van der Maarel
references: Int Immunol. 2004 Oct;16(10):1439-49
references: 15314041
references: J Biol Chem. 2002 Jun 7;277(23):20409-14
references: 11919202
references: Cell. 1999 Oct 29;99(3):247-57
references: 10555141
references: Oncogene. 1998 Nov 12;17(19):2473-84
references: 9824158
references: Pediatrics. 2007 Nov;120(5):e1341-4
references: 17908720
references: Science. 1997 Apr 25;276(5312):589-92
references: 9110977
references: J Med Genet. 2008 Feb;45(2):93-9
references: 17893117
references: J Med Genet. 1988 Mar;25(3):173-80
references: 3351904
references: Am J Med Genet A. 2004 Sep 1;129A(3):290-3
references: 15326630
references: PLoS One. 2010 Jun 29;5(6):e11364
references: 20613881
references: Genome Biol. 2009;10(3):R25
references: 19261174
references: Nature. 2005 Feb 24;433(7028):826-33
references: 15729333
references: Hum Mol Genet. 1993 Jun;2(6):731-5
references: 8102570
references: Genome Biol. 2005;6(10):R82
references: 16207353
references: Biochim Biophys Acta. 2001 May 28;1519(1-2):13-29
references: 11406267
references: Nat Immunol. 2006 Apr;7(4):392-400
references: 16491076
references: Nature. 2004 Dec 2;432(7017):635-9
references: 15577913
references: Hum Mol Genet. 2001 Dec 1;10(25):2917-31
references: 11741835
references: Hum Mutat. 2000 Dec;16(6):509-17
references: 11102980
references: Hum Mol Genet. 2003 Oct 1;12(19):2559-67
references: 12925568
references: J Med Genet. 1993 May;30(5):429-32
references: 8320711
references: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7418-25
references: 15833813
references: Blood. 2004 Apr 1;103(7):2683-90
references: 14645008
references: Hum Genet. 1995 Oct;96(4):411-6
references: 7557962
references: Hum Mutat. 2005 Jan;25(1):56-63
references: 15580563
references: Mol Cell Biol. 2005 Jan;25(2):554-62
references: 15632058
references: Hum Genet. 1997 Jun;99(6):738-45
references: 9187666
references: Hum Mol Genet. 2008 Mar 1;17(5):690-709
references: 18029387
references: Am J Med Genet A. 2007 Sep 1;143A(17):2052-7
references: 17702009
references: Nat Immunol. 2005 Apr;6(4):373-81
references: 15750595
references: Nature. 1999 Nov 11;402(6758):187-91
references: 10647011
references: Genes Dev. 1994 Jul 15;8(14):1664-77
references: 7958847
references: Mol Cell Biol. 2004 Dec;24(23):10456-69
references: 15542853
references: Cell Growth Differ. 1995 Dec;6(12):1495-503
references: 9019154
references: Immunity. 2000 Aug;13(2):199-212
references: 10981963
references: Development. 2006 Mar;133(6):1183-92
references: 16501171
references: Immunol Lett. 2007 Jan 15;108(1):1-9
references: 17084908
references: Science. 1987 Jun 19;236(4808):1567-70
references: 2884728
references: Genes Dev. 2000 Jul 15;14(14):1810-23
references: 10898795
references: Am J Med Genet A. 2005 Jul 1;136(1):31-7
references: 15952214
references: J Allergy Clin Immunol. 2001 Aug;108(2):310-2
references: 11496256
references: Am J Hum Genet. 1998 Sep;63(3):803-9
references: 9718351
references: Cytogenet Cell Genet. 2000;89(1-2):121-8
references: 10894953
references: Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16546-51
references: 17923676
references: EMBO J. 1995 Dec 15;14(24):6209-17
references: 8557040
references: J Neurol Sci. 2004 Jan 15;217(1):107-10
references: 14675617
references: Bioinformatics. 2009 Aug 15;25(16):2078-9
references: 19505943
references: Nat Genet. 2010 Jan;42(1):30-5
references: 19915526