Mutations in Z8T824 Are Associated with Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome Type 2

JC de Greef, Johnny Wang, J Balog, JT Dunnen, RR Frants, KR Straasheijm, C Aytekin, Mirjam van der Burg, L Duprez, A Ferster, AR Gennery, G Gimelli, I Reisli, C Schuetz, A Schulz, DFCM Smeets, Y Sznajer, C Wijmenga, MC van Eggermond, MM ten DamAC Lankester, MJD van Tol, PJ van den Elsen, CM Weemaes, SM van der Maarel

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120 Citations (Scopus)

Abstract

Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICE) 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 (1072) 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 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.
Original languageUndefined/Unknown
Pages (from-to)796-804
Number of pages9
JournalAmerican Journal of Human Genetics
Volume88
Issue number6
DOIs
Publication statusPublished - 2011

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