|
|||||
|
|
Structural analysis of the impact of a novel androgen receptor gene mutation in two adult patients with mild androgen insensitivity syndrome |
|
| Authors: | Mirella Hage Delphine Drui Bruno Francou Sandra Mercier Anne Guiochon-Mantel Joelle Belaisch-Allart Yann Péréon Laure Cazabat Philippe De Mazancourt Marie Laure Raffin-Sanson |
| Affiliation: | 1. Centre Hospitalier Universitaire Ambroise Paré, Service d’Endocrinologie Diabétologie et Nutrition, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt, France;2. Centre Hospitalier Universitaire Nantes, Service d’Endocrinologie, L'institut du Thorax, Nantes, France;3. Centre Hospitalier Universitaire Bicêtre, Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France;4. Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, L'institut du Thorax, Nantes, France;5. Centre Hospitalier Universitaire Bicêtre, Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France Inserm UMR 1185, Faculté de médecine Paris Saclay, Université Paris-Saclay, le Kremlin-Bicêtre, France;6. Centre Hospitalier des Quatre Villes, Service de Gynécologie-Obstétrique et Médecine de la Reproduction, Sèvres, France;7. Centre Hospitalier Universitaire Nantes, Centre de Référence Maladies Neuromusculaires Nantes-Angers, Hôtel-Dieu, Nantes, France;8. Centre Hospitalier Universitaire Ambroise Paré, Service d’Endocrinologie Diabétologie et Nutrition, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt, France EA4340, Université de Versailles Saint-Quentin-en-Yvelines, UFR des sciences de la santé Simone Veil, Montigny-le-Bretonneux, France;9. Centre Hospitalier Universitaire Ambroise Paré, Laboratoire de Biochimie-Génétique Moléculaire, UMR1179, Boulogne Billancourt, France |
| Abstract: | Androgen receptor gene (AR) mutations are responsible for androgen insensitivity syndrome (AIS) presenting with a clinical phenotype that ranges from gynaecomastia and/ or infertility in mild AIS (MAIS) to complete testicular feminisation in complete AIS. We report a novel AR gene mutation in two unrelated adult patients with MAIS and we studied its functional impact using 3D modelling. Patient 1, referred for infertility, presented with gynaecomastia, mild hypospadias and bilateral testicular hypotrophy contrasting with high testosterone levels, an elevated FSH, an elevated androgen sensitivity index (ASI) and oligoasthenoteratospermia. In vitro fertilisation and intracytoplasmic sperm injection resulted in a successful twin pregnancy. Patient 2 referred for a decrease in athletic performance had surgically treated gynaecomastia, oligoasthenospermia, high testosterone levels and an elevated ASI. Despite his impaired spermogram, he fathered two children without assisted reproductive technology. AR gene sequencing in the two patients revealed a common novel missense mutation, Ala699Thr, in exon 4 within the ligand-binding domain. 3D modelling studies showed that this mutation may impact dimer stability upon ligand binding or may affect allosteric changes upon dimerisation. This study illustrates the value of structural analysis for the functional study of mutations and expands the database of AR gene mutations. |
| Keywords: | androgen insensitivity gynaecomastia infertility novel mutation receptor dimerisation |