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Am J Hum Genet. 2011 Jun 10;88(6):796-804. doi: 10.1016/j.ajhg.2011.04.018. Epub 2011 May 19.

Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2.

Author information

1
Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
2
Department of Pediatric Immunology, Dr. Sami Ulus Children's Health and Diseases Training and Research Center, 06080 Ankara, Turkey.
3
Department of Immunology, Erasmus Medical Center, University Medical Center Rotterdam, 3015 CE Rotterdam, The Netherlands.
4
Department of Medical Genetics, Hôpital Erasme-Université Libre de Bruxelles, 1070 Brussels, Belgium.
5
Department of Paediatrics, Haemato-Oncology Unit, Hôpital Universitaire des Enfants Reine Fabiola- Université Libre de Bruxelles, 1020 Brussels, Belgium.
6
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.
7
Laboratorio di Citogenetica, Instituto Giannina Gaslini, 16148 Genoa, Italy.
8
Department of Pediatric Immunology and Allergy, Selcuk University, 42003 Konya, Turkey.
9
Department of Pediatrics and Adolescent Medicine, University Hospital Ulm, 89075 Ulm, Germany.
10
Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6526 GA Nijmegen, The Netherlands.
11
Pediatric Clinical Genetics and Center for Human Genetics, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), 1020 Brussels, Belgium.
12
Genetics Department, University Medical Center and Groningen University, 9713 GZ Groningen, The Netherlands.
13
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
14
Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
15
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.
16
Department of Paediatric Infectious Diseases and Immunology, Radboud University Nijmegen Medical Centre, 6526 GA Nijmegen, The Netherlands.
17
Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. Electronic address: maarel@lumc.nl.

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.

PMID:
21596365
PMCID:
PMC3113345
DOI:
10.1016/j.ajhg.2011.04.018
[Indexed for MEDLINE]
Free PMC Article

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