Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome
Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome
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DOI：
10.1086/505693
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发表时间：
2006-08-01
影响因子：
9.8
通讯作者：
van Bokhoven, Hans
中科院分区：
文献类型：
--
作者：
Kleefstra, Tjitske;Brunner, Han G.;van Bokhoven, Hans
最近已经确定了一种临床上可识别的 9q 亚端粒缺失综合征。这些患者的常见特征是严重智力低下、肌张力低下、短头畸形、扁脸伴距离过远、联锁、鼻孔前倾、丘比特弓或上唇凹陷、下唇外翻、下颌前突、巨舌症、圆锥干心脏缺陷和行为问题。据估计，造成这种 9q 亚端粒体缺失 (9q(-)) 综合征的最小关键区域 < 1 Mb，包含常染色质组蛋白甲基转移酶 1 基因 (EHMT1)。先前的研究表明，EHMT1 的单倍体不足是 9q 亚端粒缺失综合征的原因。我们对 23 名临床表现类似 9q 亚端粒缺失综合征的患者进行了 EHMT1 基因的全面突变分析。该分析揭示了构成 EHMT1 基因的另外三个微缺失，其中包括一个减少了该综合征关键区域的间质缺失。最重要的是，我们在具有典型 9q(-) 表型的患者的 EHMT1 基因中发现了两种从头突变——一种无义突变和一种移码突变。这些结果证实 EHMT1 的单倍体不足是 9q 亚端粒缺失综合征的原因。
A clinically recognizable 9q subtelomeric deletion syndrome has recently been established. Common features seen in these patients are severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia, conotruncal heart defects, and behavioral problems. The minimal critical region responsible for this 9q subtelomeric deletion (9q(-)) syndrome has been estimated to be < 1 Mb and comprises the euchromatin histone methyl transferase 1 gene (EHMT1). Previous studies suggested that haploinsufficiency for EHMT1 is causative for 9q subtelomeric deletion syndrome. We have performed a comprehensive mutation analysis of the EHMT1 gene in 23 patients with clinical presentations reminiscent of 9q subtelomeric deletion syndrome. This analysis revealed three additional microdeletions that comprise the EHMT1 gene, including one interstitial deletion that reduces the critical region for this syndrome. Most importantly, we identified two de novo mutations-a nonsense mutation and a frameshift mutation-in the EHMT1 gene in patients with a typical 9q(-) phenotype. These results establish that haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome.