ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat–Wilson syndrome
| Autor: | Constantin Yanicostas, Michel Goossens, Jeanne Amiel, David Mowat, Irina Giurgea, Linda Goodwin, Marlène Rio, Nadia Soussi-Yanicostas, Jamal Ghoumid, Seyedeh Maryam Alavi-Naini, Patrick Raymond, Nadege Bondurand, Stanislas Lyonnet, Loïc Drévillon, Audrey Briand-Suleau, Mayssa Nasser |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Microcephaly Transcription Genetic Mowat–Wilson syndrome Molecular Sequence Data Mutation Missense Biology Cell Line Intellectual Disability Gene Order Genetics medicine Animals Humans Missense mutation Amino Acid Sequence Hirschsprung Disease Molecular Biology Gene Alleles Zebrafish Genetics (clinical) Zinc Finger E-box Binding Homeobox 2 Homeodomain Proteins Corpus Callosum Agenesis Facies Zinc Fingers Morphant DNA General Medicine medicine.disease Stop codon Repressor Proteins Disease Models Animal Phenotype Female Protein Binding |
| Zdroj: | Human Molecular Genetics. 22:2652-2661 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddt114 |
| Popis: | Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple con- genital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, con- otruncal 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 charac- terized 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 develop- ment. 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. |
| Databáze: | OpenAIRE |
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