Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is a rare autosomal recessive disorder caused by mutations in either DNMT3B, ZBTB24, CDCA7, HELLS or an unknown gene(s). Among the known causative genes, ZBTB24 encodes a member of the BTB-zinc finger (ZF) transcription factor family. The protein possesses a BTB domain, an AT-hook and eight C2H2 ZF motifs. All ZBTB24 mutations reported in ICF patients are predicted to disrupt at least one ZF motif. Here, we show that both AT-hook and distinct ZF motifs, particularly the 6th motif, of human and mouse ZBTB24 proteins are important for their heterochromatin localization. On the other hand, the 6th and 7th ZF motifs, and not the AT-hook or the BTB domain, of the human and mouse proteins are essential for transcriptional activation of CDCA7, another ICF causative gene and a known target of ZBTB24. By deletion analysis of the human CDCA7 promoter, we show that two motifs for ZBTB24 binding are important for transcriptional activation of this gene. These results reveal the evolutionarily conserved domains and motifs important for the biological function of ZBTB24, which provides a basis for understanding the molecular mechanisms underlying the pathogenesis of ICF syndrome.

中文翻译：

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鉴定ZBTB24蛋白结构域和异染色质定位和转录激活的基序。

免疫缺陷，着丝粒不稳定，面部异常（ICF）综合征是一种罕见的常染色体隐性遗传疾病，由DNMT3B，ZBTB24，CDCA7，HELLS或未知基因突变引起。在已知的致病基因中，ZBTB24编码BTB-锌指（ZF）转录因子家族的成员。该蛋白具有一个BTB结构域，一个AT钩和8个C2H2 ZF基序。据预测，ICF患者中报告的所有ZBTB24突变都会破坏至少一个ZF基序。在这里，我们显示人和小鼠ZBTB24蛋白的AT钩和独特的ZF模体，特别是第6个模体，对于它们的异染色质定位都很重要。另一方面，人和小鼠蛋白的第6个和第7个ZF基序，而不是AT钩或BTB结构域，对于CDCA7的转录激活至关重要，另一个ICF致病基因和ZBTB24的已知靶标。通过人类CDCA7启动子的缺失分析，我们显示ZBTB24结合的两个基序对于该基因的转录激活很重要。这些结果揭示了对于ZBTB24的生物学功能重要的进化保守结构域和基序，这为理解ICF综合征发病机理的分子机制提供了基础。