Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of theSOX9TESCO enhancer
| العنوان: | Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of theSOX9TESCO enhancer |
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| المؤلفون: | Anthony Daniel Bird, Andrew H. Sinclair, Vincent R. Harley, Brittany Croft, Faustine Declosmenil, Peter Koopman, Louisa Mabel Ludbrook, Francis Poulat, Ken McElreavey, Kevin Christopher Knower, Brett Daniel Fisher, Janelle Ryan, Anu Bashamboo, Rajini Sreenivasan |
| المساهمون: | University of Melbourne, Monash University [Victoria, Australia], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hudson Institute of Medical Research [Clayton], Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP), Murdoch Children’s Research Institute [Melbourne, Australia], Institute for Molecular Bioscience, University of Queensland [Brisbane], This work was supported by the National Health and Medical Research Council of Australia (NHMRC) Program Grants 334314 and 546517 to V.H., P.K., and A.S. and by the Victorian Government's Operational Infrastructure Support Program (OIS). R.S. was supported by an Australian Postgraduate Award. B.C. is supported by an Australian Government Research Training Program Scholarship, through Monash University. V.H., P.K.. and A.S. are supported by NHMRC Research Fellowships. |
| المصدر: | Human Mutation Human Mutation, 2018, 39 (12), pp.1861-1874. ⟨10.1002/humu.23603⟩ |
| بيانات النشر: | Hindawi Limited, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Steroidogenic factor 1, MESH: Sequence Analysis, DNA, testis-specific enhancer of SOX9, Mutant, sex determination, DSD, Ligands, Steroidogenic Factor 1, medicine.disease_cause, 0302 clinical medicine, MESH: Child, MESH: Ligands, Disorders of sex development, Child, Genetics (clinical), Regulation of gene expression, Genetics, Mutation, MESH: Infant, Newborn, MESH: Disorder of Sex Development, 46,XY, SOX9 Transcription Factor, MESH: Infant, MESH: Gene Expression Regulation, Enhancer Elements, Genetic, Testis determining factor, MESH: HEK293 Cells, Child, Preschool, SF-1, SOX9, Protein Binding, Adult, MESH: Mutation, Adolescent, 030209 endocrinology & metabolism, Biology, MESH: SOX9 Transcription Factor, 03 medical and health sciences, MESH: Computer Simulation, medicine, MESH: Protein Binding, Humans, Computer Simulation, Enhancer, MESH: Adolescent, MESH: Humans, Disorder of Sex Development, 46,XY, MESH: Child, Preschool, Infant, Newborn, Infant, MESH: Adult, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Sequence Analysis, DNA, MESH: Steroidogenic Factor 1, medicine.disease, MESH: Male, HEK293 Cells, 030104 developmental biology, Gene Expression Regulation, MESH: Enhancer Elements, Genetic |
| الوصف: | International audience; Nuclear receptor subfamily 5 group A member 1/Steroidogenic factor 1 (NR5A1; SF-1; Ad4BP) mutations cause 46,XY disorders of sex development (DSD), with phenotypes ranging from developmentally mild (e.g., hypospadias) to severe (e.g., complete gonadal dysgenesis). The molecular mechanism underlying this spectrum is unclear. During sex determination, SF-1 regulates SOX9 (SRY [sex determining region Y]-box 9) expression. We hypothesized that SF-1 mutations in 46,XY DSD patients affect SOX9 expression via the Testis-specific Enhancer of Sox9 core element, TESCO. Our objective was to assess the ability of 20 SF-1 mutants found in 46,XY DSD patients to activate TESCO. Patient DNA was sequenced for SF-1 mutations and mutant SF-1 proteins were examined for transcriptional activity, protein expression, sub-cellular localization and in silico structural defects. Fifteen of the 20 mutants showed reduced SF-1 activation on TESCO, 11 with atypical sub-cellular localization. Fourteen SF-1 mutants were predicted in silico to alter DNA, ligand or cofactor interactions. Our study may implicate aberrant SF-1-mediated transcriptional regulation of SOX9 in 46,XY DSDs. |
| تدمد: | 1059-7794 1098-1004 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::85bf3bb6c1222048f9bebd0d6dd26b0bTest https://doi.org/10.1002/humu.23603Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....85bf3bb6c1222048f9bebd0d6dd26b0b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10597794 10981004 |
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