Luciani Judith J, Depetris Danielle, Missirian Chantal, Mignon-Ravix Cécile, Metzler-Guillemain Catherine, Megarbane André, Moncla Anne, Mattei Marie-Geneviève
Inserm U 491, Faculté de Médecine, Marseille, France.
Eur J Hum Genet. 2005 Jan;13(1):41-51. doi: 10.1038/sj.ejhg.5201293.
The Immunodeficiency, Centromeric instability, and Facial (ICF) syndrome is a rare autosomal recessive disorder that results from mutations in the DNMT3B gene, encoding a DNA-methyltransferase that acts on GC-rich satellite DNAs. This syndrome is characterized by immunodeficiency, facial dysmorphy, mental retardation of variable severity and chromosomal abnormalities that essentially involve juxtacentromeric heterochromatin of chromosomes 1 and 16. These abnormalities demonstrate that hypomethylation of satellite DNA can induce alterations in the structure of heterochromatin. In order to investigate the effect of DNA hypomethylation on heterochromatin organization, we analyzed the in vivo distribution of HP1 proteins, essential components of heterochromatin, in three ICF patients. We observed that, in a large proportion of ICF G2 nuclei, all HP1 isoforms show an aberrant signal concentrated into a prominent bright focus that co-localizes with the undercondensed 1qh or 16qh heterochromatin. We found that SP100, SUMO-1 and other proteins from the promyelocytic leukemia nuclear bodies (NBs) form a large body that co-localizes with the HP1 signal. This is the first description of altered nuclear distribution of HP1 proteins in the constitutional ICF syndrome. Our results show that satellite DNA hypomethylation does not prevent HP1 proteins from associating with heterochromatin. They suggest that, at G2 phase, HP1 proteins are involved in the heterochromatin condensation and may therefore remain concentrated at these sites until the condensation is complete. They also indicate that proteins from the NB could play a role in this process. Finally, satellite DNA length polymorphism could affect the efficiency of heterochromatin condensation and thus contribute to the variability of the ICF phenotype.
免疫缺陷、着丝粒不稳定和面部（ICF）综合征是一种罕见的常染色体隐性疾病，由DNMT3B基因突变引起，该基因编码一种作用于富含GC的卫星DNA的DNA甲基转移酶。该综合征的特征是免疫缺陷、面部畸形、严重程度不一的智力发育迟缓以及染色体异常，这些异常主要涉及1号和16号染色体的近着丝粒异染色质。这些异常表明卫星DNA的低甲基化可诱导异染色质结构改变。为了研究DNA低甲基化对异染色质组织的影响，我们分析了三名ICF患者体内异染色质的重要组成部分HP1蛋白的分布。我们观察到，在大部分ICF G2细胞核中，所有HP1亚型均显示异常信号，集中在一个突出的明亮焦点上，该焦点与未浓缩的1qh或16qh异染色质共定位。我们发现，来自早幼粒细胞白血病核体（NBs）的SP100、SUMO-1和其他蛋白形成一个与HP1信号共定位的大核体。这是对先天性ICF综合征中HP1蛋白核分布改变的首次描述。我们的结果表明，卫星DNA低甲基化并不妨碍HP1蛋白与异染色质结合。结果提示，在G2期，HP1蛋白参与异染色质浓缩，因此可能会一直集中在这些位点，直到浓缩完成。结果还表明，来自核体的蛋白可能在此过程中发挥作用。最后，卫星DNA长度多态性可能影响异染色质浓缩效率，从而导致ICF表型的变异性。
