Yamada Yasukazu, Nomura Noriko, Yamada Kenichiro, Matsuo Mari, Suzuki Yuka, Sameshima Kiyoko, Kimura Reiko, Yamamoto Yuto, Fukushi Daisuke, Fukuhara Yayoi, Ishihara Naoko, Nishi Eriko, Imataka George, Suzumura Hiroshi, Hamano Shin-Ichiro, Shimizu Kenji, Iwakoshi Mie, Ohama Kazunori, Ohta Akira, Wakamoto Hiroyuki, Kajita Mitsuharu, Miura Kiyokuni, Yokochi Kenji, Kosaki Kenjiro, Kuroda Tatsuo, Kosaki Rika, Hiraki Yoko, Saito Kayoko, Mizuno Seiji, Kurosawa Kenji, Okamoto Nobuhiko, Wakamatsu Nobuaki
Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
Am J Med Genet A. 2014 Aug;164A(8):1899-908. doi: 10.1002/ajmg.a.36551. Epub 2014 Apr 8.
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.
莫瓦特-威尔逊综合征（MWS）是一种多发性先天性异常综合征，其特征为中度或重度智力残疾、特征性面容、小头畸形、癫痫、胼胝体发育不全或发育不良、先天性心脏缺陷、先天性巨结肠病以及泌尿生殖系统/肾脏异常。它由从头发生的杂合性功能丧失突变引起，包括2q22处ZEB2基因的无义突变、移码突变和缺失。ZEB2编码由1214个氨基酸组成的锌指E盒结合同源框2蛋白。在此，我们报告了来自日本40例新确诊的MWS患者的13个无义突变和27个移码突变。尽管所有携带无义突变和移码突变的日本MWS患者的临床发现与先前关于由ZEB2无义突变、移码突变和缺失引起的MWS的综述报告非常相似，但小头畸形、先天性巨结肠病以及泌尿生殖系统/肾脏异常的发生率较低。患者携带的突变跨越野生型ZEB2中氨基酸55至1204之间的区域。患者之间没有明显的基因型-表型相关性。一项转染研究表明，携带p.D1204Rfs*29突变的最长形式的突变ZEB2蛋白的细胞水平显著降低。结果表明，ZEB2的3'端移码突变由于ZEB2的不稳定性而导致MWS。
