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.
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Acknowledgements
We would like to thank all patients and their families for participation in this study. We thank Dr Masaki Okano for providing us with the Dnmt TKO mouse ES cells. We are also grateful for the useful advice of Drs Takashi Sado, Yufeng Li, Tomoko Ichiyanagi and Kei Fukuda, and the technical assistance of Mr. Hiroyasu Furuumi. This study was supported by JSPS KAKENHI 23249019 and a research grant from the Uehara Memorial Foundation.
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Nitta, H., Unoki, M., Ichiyanagi, K. et al. Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients. J Hum Genet 58, 455–460 (2013). https://doi.org/10.1038/jhg.2013.56
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DOI: https://doi.org/10.1038/jhg.2013.56
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