Differential functional effects of novel mutations of the transcription factor FOXL2 in BPES patients
| العنوان: | Differential functional effects of novel mutations of the transcription factor FOXL2 in BPES patients |
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| المؤلفون: | Lara Moumné, Reiner A. Veitia, Jeyabalan Nallathambi, Corinne Lesaffre, Pj Eswari Pandaranayaka, Frank Batista, Bérénice A. Benayoun, Sankaran Krishnaswamy, Kim Usha, Paul Laissue, Periasamy Sundaresan |
| المصدر: | Human Mutation. 29:E123-E131 |
| بيانات النشر: | Hindawi Limited, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Forkhead Box Protein L2, Male, Mutant, Blepharophimosis, Primary Ovarian Insufficiency, Biology, medicine.disease_cause, Frameshift mutation, Forkhead Transcription Factors, Chlorocebus aethiops, Genetics, medicine, Animals, Humans, Missense mutation, Child, Frameshift Mutation, Transcription factor, Genetics (clinical), Mutation, Infant, Protein Structure, Tertiary, Forkhead box L2, Child, Preschool, COS Cells, Female, Binding domain |
| الوصف: | Mutations of the transcription factor FOXL2, involved in cranio-facial and ovarian development lead to the Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) in human. Here, we describe nine mutations in the open reading frame of FOXL2. Six of them are novel: c.292T>A (p.Trp98Arg), c.323T>C (p.Leu108Pro), c.650C>G (p.Ser217Cys) and three frameshifts. We have performed localization and functional studies for three of them. We have observed a strong cytoplasmic mislocalization induced by the missense mutation p.Leu108Pro located in the forkhead (FKH) domain of FOXL2. In line with this, transcriptional activity assays confirmed the loss-of-function induced by this variant. Interestingly, the novel mutation p.Ser217Cys, mapping between the FKH and the polyalanine domain of FOXL2 and producing a mild eyelid phenotype, led to normal localization and transactivation. We have also modeled the structure of the FKH domain to explore the potential structural impact of the mutations reported here and other previously reported ones. This analysis shows that mutants can be sorted into two classes: those that potentially alter protein-protein interactions and those that might disrupt the interactions with DNA. Our findings reveal new insights into the molecular effects of FOXL2 mutations, especially those affecting the FKH binding domain. (c) 2008 Wiley-Liss, Inc. |
| تدمد: | 1098-1004 1059-7794 |
| DOI: | 10.1002/humu.20809 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0217b630ca5daa3b2e71376025d9383d https://doi.org/10.1002/humu.20809 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0217b630ca5daa3b2e71376025d9383d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10981004 10597794 |
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| DOI: | 10.1002/humu.20809 |