The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations

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.

Keywords: Mowat-Wilson syndrome; ZEB2; frameshift mutation; nonsense mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Cell Line
  • Child
  • Child, Preschool
  • Codon, Nonsense
  • Facies
  • Female
  • Frameshift Mutation
  • Gene Expression
  • Genetic Association Studies*
  • Hirschsprung Disease / diagnosis
  • Hirschsprung Disease / epidemiology
  • Hirschsprung Disease / genetics*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Infant
  • Intellectual Disability / diagnosis
  • Intellectual Disability / epidemiology
  • Intellectual Disability / genetics*
  • Japan
  • Male
  • Microcephaly / diagnosis
  • Microcephaly / epidemiology
  • Microcephaly / genetics*
  • Phenotype
  • Prevalence
  • Protein Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Young Adult
  • Zinc Finger E-box Binding Homeobox 2


  • Codon, Nonsense
  • Homeodomain Proteins
  • RNA, Messenger
  • Repressor Proteins
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2

Supplementary concepts

  • Mowat-Wilson syndrome