title: 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.
authors: AP-HP, Hôpital H. Mondor—A. Chenevier, Service de Biochimie et Génétique, Créteil, France
authors: Jamal
authors: J
authors: Ghoumid
authors: Loïc
authors: L
authors: Drevillon
authors: Seyedeh Maryam
authors: SM
authors: Alavi-Naini
authors: Nadège
authors: N
authors: Bondurand
authors: Marlène
authors: M
authors: Rio
authors: Audrey
authors: A
authors: Briand-Suleau
authors: Mayssa
authors: M
authors: Nasser
authors: Linda
authors: L
authors: Goodwin
authors: Patrick
authors: P
authors: Raymond
authors: Constantin
authors: C
authors: Yanicostas
authors: Michel
authors: M
authors: Goossens
authors: Stanislas
authors: S
authors: Lyonnet
authors: David
authors: D
authors: Mowat
authors: Jeanne
authors: J
authors: Amiel
authors: Nadia
authors: N
authors: Soussi-Yanicostas
authors: Irina
authors: I
authors: Giurgea
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D019066:Facies; D005260:Female; D023061:Gene Order; D006627:Hirschsprung Disease / Q000235:genetics*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015027:Zebrafish; D000074165:Zinc Finger E-box Binding Homeobox 2; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D004247:DNA