• Yasukazu Yamada, Noriko Nomura, Kenichiro Yamada, Mari Matsuo, Yuka Suzuki, Kiyoko Sameshima, Reiko Kimura, Yuto Yamamoto, Daisuke Fukushi, Yayoi Fukuhara, Naoko Ishihara, Eriko Nishi, George Imataka, Hiroshi Suzumura, Shin-Ichiro Hamano, Kenji Shimizu, Mie Iwakoshi, Kazunori Ohama, Akira Ohta, Hiroyuki Wakamoto, Mitsuharu Kajita, Kiyokuni Miura, Kenji Yokochi, Kenjiro Kosaki, Tatsuo Kuroda, Rika Kosaki, Yoko Hiraki, Kayoko Saito, Seiji Mizuno, Kenji Kurosawa, Nobuhiko Okamoto, and Nobuaki Wakamatsu.
• Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
• Am. J. Med. Genet. A. 2014 Aug 1;164A(8):1899-908.

AbstractMowat-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.© 2014 Wiley Periodicals, Inc.

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