Three novel DNMT3B mutations in Japanese patients with ICF syndrome
Three novel DNMT3B mutations in Japanese patients with ICF syndrome
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DOI：
10.1002/ajmg.10658
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发表时间：
2002-09-15
期刊：
影响因子：
--
通讯作者：
Sasaki, H
中科院分区：
文献类型：
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作者：
Shirohzu, H;Kubota, T;Sasaki, H
ICF综合征是一种罕见的常染色体隐性遗传疾病，以免疫缺陷、着丝粒不稳定和面部畸形为特征。它是由从头DNA甲基转移酶基因DNMT 3B突变引起的。我们在这里报告的前三个日本ICF综合征的两个无关的家庭。所有患者均有典型的面部畸形和免疫球蛋白A（伊加）缺乏，但无明显的智力低下。外周血淋巴细胞的细胞遗传学分析显示染色体异常，包括多放射状构型和1号和16号染色体着丝粒周围异染色质的拉伸。还观察到经典卫星2 DNA的低甲基化。DNMT 3B的突变分析揭示了三种新的突变：来自第一个家族的患者1是无义突变（Q42 Term）和错义突变（R832 Q）的复合杂合子;来自第二个家族的患者2和3都是错义突变（S282 P）的纯合子。R832 Q突变发生在保守的甲基转移酶结构域，因此可能直接影响酶活性。另一方面，S282 P突变发生在PWWP结构域附近，推测其参与蛋白质-蛋白质相互作用。这是第一个错义突变映射到蛋白质的N-末端一半，表明该区域在DNMT 3B酶的调节中起着重要作用。(C)2002 Wiley-Liss，Inc.
ICF syndrome is a rare autosomal recessive disorder characterized by immunodeficiency, centromeric instability, and facial anomalies. It is caused by mutations in a de novo DNA methyltransferase gene, DNMT3B. We here report the first three Japanese cases of ICF syndrome from two unrelated families. All patients had typical facial dysmorphism and immunoglobulin A (IgA) deficiency, but none of them had apparent mental retardation. Cytogenetic analysis of peripheral blood lymphocytes showed chromosomal abnormalities, including multiradial configurations and a stretching of the pericentromeric heterochromatin of chromosomes 1 and 16. Hypomethylation of classical satellite 2 DNA was also observed. Mutation analyses of DNMT3B revealed three novel mutations: patient 1 from the first family was a compound heterozygote for a nonsense mutation (Q42Term) and a missense mutation (R832Q); patients 2 and 3 from the second family were both homozygous for a missense mutation (S282P). The R832Q mutation occurred within the conserved methyltransferase domain, and thus may affect the enzyme activity directly. The S282P mutation, on the other hand, occurred close to the PWWP domain, which is presumably involved in protein-protein interaction. This is the first missense mutation mapped to the N-terminal half of the protein, suggesting that the region plays an important role in the regulation of the DNMT3B enzyme. (C) 2002 Wiley-Liss, Inc.