Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients

Abstract

Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder that shows DNA hypomethylation at pericentromeric satellite-2 and -3 repeats in chromosomes 1, 9 and 16. ICF syndrome is classified into two groups: type 1 (ICF1) patients have mutations in the DNMT3B gene and about half of type 2 (ICF2) patients have mutations in the ZBTB24 gene. Besides satellite-2 and -3 repeats, α-satellite repeats are also hypomethylated in ICF2. In this study, we report three novel ZBTB24 mutations in ICF2. A Japanese patient was homozygous for a missense mutation (C383Y), and a Cape Verdean patient was compound heterozygous for a nonsense mutation (K263X) and a frame-shift mutation (C327W fsX54). In addition, the second Japanese patient was homozygous for a previously reported nonsense mutation (R320X). The C383Y mutation abolished a C2H2 motif in one of the eight zinc-finger domains, and the other three mutations caused a complete or large loss of the zinc-finger domains. Our immunofluorescence analysis revealed that mouse Zbtb24 proteins possessing a mutation corresponding to either C383Y or R320X are mislocalized from pericentrometic heterochromatin, suggesting the importance of the zinc-finger domains in proper intranuclear localization of this protein. We further revealed that the proper localization of wild-type Zbtb24 protein does not require DNA methylation.

Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology

“…Most patients were described earlier [11,12,25-27] except for five newly enrolled patients (Table  1). The ICF B-lymphoblastoid and fibroblasts named here pCor were obtained from the Coriell Cell Repositories (USA) ( http://ccr.coriell.org/).…”

“…Patients pW, pT and P5 were described earlier [11,25,26]. Patients P7 and P8 were recently classified as ICF2 patients [27]. Patients pC, pS, pU and pN were classified as ICFX patients since sequence analysis of DNMT3B and ZBTB24 genes performed as previously described [12,27] did not reveal any mutation in their coding sequences.…”

“…For these patients, primary immunodeficiency and hypomethylation at satellite repeats are detailed in Additional files 3 and 4. These patients were classified as ICF1 patients (Necker Hospital, Paris, France) based on mutations found in DNMT3B using previously described sequencing methods [12,27]. Written informed consent was obtained from the parents of the patients.…”

Characterization of How DNA Modifications Affect DNA Binding by C2H2 Zinc Finger Proteins

“…Kaiso is the first known methyl-binding ZnF protein that belongs to the BTB/POZ family (Prokhortchouk et al, 2001), which also includes ZBTB24, whose mutations are associated with i mmunodeficiency, c entromeric instability, and f acial anomalies (ICF) syndrome (Cerbone et al, 2012; Chouery et al, 2012; de Greef et al, 2011; Nitta et al, 2013), a disease also caused by mutations in a DNA methyl-transferase gene, DNMT3B (Hansen et al, 1999; Okano et al, 1999; Shirohzu et al, 2002; Xu et al, 1999). Recently, ZnF DNA-binding domains from five proteins, Kaiso, Zfp57, Klf4, Egr1, and WT1, have been structurally analyzed in complex with their respective methylated DNA elements (Buck-Koehntop et al, 2012; Hashimoto et al, 2014; Liu et al, 2014; Liu, Toh, Sasaki, Zhang, & Cheng, 2012; Zandarashvili, White, Esadze, & Iwahara, 2015), allowing comparison to other 5mC-binding proteins.…”

Novel ZBTB24 Mutation Associated with Immunodeficiency, Centromere Instability, and Facial Anomalies Type-2 Syndrome Identified in a Patient with Very Early Onset Inflammatory Bowel Disease

“…Up to 13 homozygous and compound heterozygous mutations of ZBTB24 have been described in patients with this syndrome, characterized by fragile heterochromatin resulting in unstable chromosomes, which is associated with immunodeficiency, most commonly hypo- or agammaglobulinemia, facial anomalies including hypertelorism, flat nasal bridge, epicanthal folds, micrognathia, and tongue protrusion, and variable intellectual disability. 11,12 Inflammatory bowel disease confirmed by endoscopic biopsy has not previously been reported with ICF2 syndrome, but IBD has been associated with other humoral immunodeficiencies defined by hypo- or agammaglobulinemia. This association has led to the use of intravenous immunoglobulin as a therapy for IBD in some refractory cases.…”