Human Molecular Genetics Advance Access published online on March 27, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn100
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Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalisation, protein aggregation and impaired transactivation
1 Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium 2 INSERM U567, Team21, Genetics and Development Department, Institut Cochin, 24 rue du Faubourg St-Jacques, 75014, Paris, France 3 CNRS UMR8104, Institut Cochin, 24 rue du Faubourg St-Jacques, 75014, Paris, France 4 Université Paris Descartes, Faculté de Médecine Cochin-Port-Royal, 24 rue du Faubourg St-Jacques, 75014, Paris, France 5 Université Denis Diderot, Paris VII, 75014 Paris, France 6 Institute of Medical Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany 7 Department of Ophthalmology, Ghent University Hospital, 9000 Ghent, Belgium
* Correspondence to: Elfride.DeBaere{at}UGent.be Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B- 9000 Ghent, Belgium, Phone: 32-9-332.5186. Fax: 32-9-332.4970
Received February 20, 2008; Revised March 25, 2008; Accepted March 25, 2008
Mutations of the FOXL2 gene have been shown tocause blepharophimosis syndrome (BPES), characterised by an eyelid malformation associated with premature ovarian failure or not. Recently, polyalanine expansions and truncating FOXL2 mutations have been shown to lead to protein mislocalisation, aggregation and altered transactivation. Here, we study the molecular consequences of 17 naturally-occurring FOXL2 missense mutations. Most of them map to the conserved DNA-binding forkhead domain (FHD). The subcellular localisation and aggregation pattern of the mutant FOXL2 proteins in COS-7 cells was variable and ranged from a diffuse nuclear distribution like the wild-type to extensive nuclear aggregation often in combination with cytoplasmic mislocalisation and aggregation. We also studied the transactivation capacity of the mutants in FOXL2 expressing granulosa-like cells (KGN). Several mutants led to a loss-of-function, while others are suspected to induce a dominant negative effect. Interestingly, one mutant that is located outside the FHD (S217F), appeared to be hypermorphic and had no effect on intracellular protein distribution. This mutation gives rise to a mild BPES phenotype. In general, missense mutations located in the FHD lead to classical BPES and cannot be correlated with expression of the ovarian phenotype. However, a potential predictive value of localisation and transactivation assays in the making of genotype-phenotype correlations is proposed. This is the first study to demonstrate that a significant number of missense mutations in the FHD of FOXL2 lead to mislocalisation, protein aggregation and altered transactivation, and to provide insights into the pathogenesis associated with missense mutations of FOXL2 in human disease.
+ These authors contributed equally to this work.
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