ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat–Wilson syndrome

Abstract

Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR). MWS is caused by de novo heterozygous mutations in the ZEB2 gene. The majority of mutations lead to haplo-insufficiency through premature stop codons or large gene deletions. Only three missense mutations have been reported so far; none of which resides in a known functional domain of ZEB2. In this study, we report and analyze the functional consequences of three novel missense mutations, p.Tyr1055Cys, p.Ser1071Pro and p.His1045Arg, identified in the highly conserved C-zinc-finger (C-ZF) domain of ZEB2. Patients' phenotype included the facial gestalt of MWS and moderate ID, but no microcephaly, heart defects or HSCR. In vitro studies showed that all the three mutations prevented binding and repression of the E-cadherin promoter, a characterized ZEB2 target gene. Taking advantage of the zebrafish morphant technology, we performed rescue experiments using wild-type (WT) and mutant human ZEB2 mRNAs. Variable, mutation-dependent, embryo rescue, correlating with the severity of patients' phenotype, was observed. Our data provide evidence that these missense mutations cause a partial loss of function of ZEB2, suggesting that its role is not restricted to repression of E-cadherin. Functional domains other than C-ZF may play a role in early embryonic development. Finally, these findings broaden the clinical spectrum of ZEB2 mutations, indicating that MWS ought to be considered in patients with lesser degrees of ID and a suggestive facial gestalt, even in the absence of congenital malformation.

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

“…Missense mutations of ZEB2 are a rare occurrence and were found in none of our cases. They have been described in the literature in association with mild presentations sharing some similarity with MWS, 31,32 although it is debatable whether most of these atypical cases should actually be classified as MWS. However, in addition to patients with missense mutations, there are a few cases also expected to behave differently than typical haploinsufficiency.…”

Zeb2: A multifunctional regulator of nervous system development

“…Human mutations in one of the two alleles of ZEB2 cause Mowat-Wilson syndrome (MWS), which is characterised by a combination of defects with variable penetrance, including severe mental retardation, microcephaly, seizures, agenesis of the corpus callosum and poor hippocampal formation, as well as other nonbrain-related congenital defects like Hirschsprung disease and heart and craniofacial defects (Cacheux et al, 2001;Dastot-Le Moal et al, 2007;Garavelli et al, 2009;Ghoumid et al, 2013;Mowat et al, 2003;Saunders et al, 2009;Wakamatsu et al, 2001;Yamada et al, 2014;Zweier et al, 2005). The diverse range of defects in MWS reflect the multifunctional nature of ZEB2 during CNS and NCC development, as well as the wide range of MWS-causing ZEB2 mutations (>100 identified to date), the majority of which cause drastic C-terminal truncations of ZEB2.…”

Sleep disturbance in Mowat–Wilson syndrome

“…Prior reports suggest MWS typically leads to at least moderate and more often severe intellectual disability Adam et al, 2006;Garavelli and Cerruti-Mainardi, 2007;Evans et al, 2012]. However, recently, cases with a milder phenotype resulting from missense mutations and partial loss of ZEB2 function have been reported [Yoneda et al, 2002;Zweier et al, 2006;Ghoumid et al, 2013;Wenger et al, 2014]. Evans et al [2012] found that compared with an age and ID-matched comparison group, people with MWS showed a high rate of oral behaviors, including bruxism, an increased rate of repetitive behaviors, and an under-reaction to pain.…”