Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene
Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene
复制标题
DOI：
10.1038/46052
复制
发表时间：
1999-11-11
期刊：
影响因子：
64.8
通讯作者：
Viegas-Péquignot, E
中科院分区：
文献类型：
--
作者：
Xu, GL;Bestor, TH;Viegas-Péquignot, E
被称为ICF综合征的隐性常染色体疾病（1-3）（免疫缺陷、着丝粒不稳定和面部异常;孟德尔遗传人类编号242860）的特征是血清免疫球蛋白水平的可变降低，这导致大多数ICF患者在成年前死于感染性疾病。轻度的面部异常包括间距过宽、耳位低、内眦赘皮和巨舌症。淋巴细胞的细胞遗传学异常是丰富的：在中期染色体中，着丝粒异染色质被大大拉长并呈线状，这与复杂的多辐射状染色体的形成有关。相同的着丝粒区域受到持续的间期自缔合，并被挤出到核泡或微核中。绝大多数染色体缺失主要发生在1号、9号和16号染色体着丝粒区的2号和3号随体上。经典的卫星DNA通常在胞嘧啶残基处高度甲基化，但在ICF综合征中，它在所有组织中几乎完全未甲基化（4）ICF综合征是已知涉及基因组甲基化模式的组成性异常的唯一遗传性疾病。在这里，我们发现5个无关的ICF患者在编码DNA甲基转移酶3B的基因的两个等位基因中都有突变（参考文献5，6）。胞嘧啶甲基化对于特定类型异染色质的组织和稳定是必不可少的，并且这种甲基化似乎是由专门用于该目的的酶进行的。
The recessive autosomal disorder known as ICF syndrome(1-3) (for immunodeficiency, centromere instability and facial anomalies; Mendelian Inheritance in Man number 242860) is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. Mild facial anomalies include hypertelorism, low-set ears, epicanthal folds and macroglossia. The cytogenetic abnormalities in lymphocytes are exuberant: juxtacentromeric heterochromatin is greatly elongated and thread-like in metaphase chromosomes, which is associated with the formation of complex multiradiate chromosomes. The same juxtacentromeric regions are subject to persistent interphase self-associations and are extruded into nuclear blebs or micronuclei. Abnormalities are largely confined to tracts of classical satellites 2 and 3 at juxtacentromeric regions of chromosomes 1, 9 and 16. Classical satellite DNA is normally heavily methylated at cytosine residues, but in ICF syndrome it is almost completely unmethylated in all tissues(4) ICF syndrome is the only genetic disorder known to involve constitutive abnormalities of genomic methylation patterns. Here we show that five unrelated ICF patients have mutations in both alleles of the gene that encodes DNA methyltransferase 3B (refs 5, 6). Cytosine methylation is essential for the organization and stabilization of a specific type of heterochromatin, and this methylation appears to be carried out by an enzyme specialized for the purpose.