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Mowat–Wilson syndrome (MOWS) is caused by  de novo  heterozygous mutation at  ZEB2  ( SIP1, ZFHX1B ) gene, and exhibit moderate to severe intellectual disability (ID), a characteristic facial appearance, epilepsy and other congenital anomalies. Establishing a murine MOWS model is important, not only for investigating the pathogenesis of this disease, but also for identifying compounds that may improve the symptoms. However, because the heterozygous  Zeb2  knockout mouse could not be maintained as a mouse line with the inbred C57BL/6 background, it was difficult to use those mice for the study of MOWS. Here, we systematically generated  de novo Zeb2  Δ ex7/+  mice by inducing the  Zeb2  mutation in the germ cells using conditional recombination system. The  de novo Zeb2  Δ ex7/+  mice with C57BL/6 background developed multiple defects relevant to MOWS, including craniofacial abnormalities, defective corpus callosum formation and the decreased number of parvalbumin interneurons in the cortex. In behavioral analyses, these mice showed reduced motor activity, increased anxiety and impaired sociability. Notably, during the Barnes maze test, immobile  Zeb2  mutant mice were observed over repeated trials. In contrast, neither the mouse line nor the  de novo Zeb2  Δ ex7/+  mice with the closed colony ICR background showed cranial abnormalities or reduced motor activities. These results demonstrate the advantages of using  de novo Zeb2  Δ ex7/+  mice with the C57BL/6 background as the MOWS model. To our knowledge, this is the first time an inducible  de novo  mutation system has been applied to murine germline cells to produce an animal model of a human congenital disease.

human molecular genetics

De novo  inbred heterozygous  Zeb2/Sip1  mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat–Wilson syndrome