Molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndrome
Objective: Androgen insensitivity syndrome (AIS) due to androgen receptor (AR) mutations creates a spectrum of clinical presentations based on residual AR function with the mildest impairment creating mild AIS (MAIS) whose undefined molecular mechanism and subtle clinical features leave it less unde...
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Bioscientifica
2024-12-01
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| Series: | Endocrine Connections |
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| author | Ravind Pandher Ruby Chang Yiqun Chang David E Hibbs Jonathan J Du Kristine McGrath Alison Heather Veena Jayadev David J Handelsman |
| author_facet | Ravind Pandher Ruby Chang Yiqun Chang David E Hibbs Jonathan J Du Kristine McGrath Alison Heather Veena Jayadev David J Handelsman |
| author_sort | Ravind Pandher |
| collection | DOAJ |
| description | Objective: Androgen insensitivity syndrome (AIS) due to androgen receptor (AR) mutations creates a spectrum of clinical presentations based on residual AR function with the mildest impairment creating mild AIS (MAIS) whose undefined molecular mechanism and subtle clinical features leave it less understood and underdiagnosed. Design: In silico modeling and in vitro androgen bioassay of the mutated AR are used to identify its structural and physiological mechanism. Clinical features and responses to high-dose testosterone treatment of three cases of MAIS across a six-generation family pedigree are described. Methods: Structural and dynamic in silico molecular modeling and in vitro yeast-based androgen bioassays of the mutant AR are employed. Three cases of MAIS with consistent (gynecomastia and micropenis) and variable (infertility) clinical features across generations are reported, and the effects of high-dose testosterone treatment are studied. Results: The missense AR exon 8 mutation (nucleotide aga → gga, p.R872G arginine to glycine), known to cause an increased ligand dissociation rate in mutant AR in binding assays, was analyzed. Modeling shows that the mutation weakens the closure energy of the ‘lid’ of the ligand-binding pocket, allowing easier ligand dissociation from the binding site but with unimpaired in vitro androgen bioactivity. High-dose testosterone treatment for 3 years in one young man caused increased virilization and height growth but was ineffective for treating micropenis. Genetic counseling allowed effective prediction of MAIS risks in progeny for carrier and noncarrier sisters. Conclusions: The differential diagnosis and clinical management of MAIS is reviewed. The novel molecular mechanism of an AR ligand-binding domain mutation in MAIS may be present in other cases of MAIS. |
| format | Article |
| id | doaj-art-d1e831accd3f4565acb7acf35e1674ce |
| institution | OA Journals |
| issn | 2049-3614 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Bioscientifica |
| record_format | Article |
| series | Endocrine Connections |
| spelling | doaj-art-d1e831accd3f4565acb7acf35e1674ce2025-08-20T02:35:29ZengBioscientificaEndocrine Connections2049-36142024-12-0114110.1530/EC-24-05671Molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndromeRavind Pandher0Ruby Chang1Yiqun Chang2David E Hibbs3Jonathan J Du4Kristine McGrath5Alison Heather6Veena Jayadev7David J Handelsman8Andrology Department, Concord, AustraliaAndrology Department, Concord, AustraliaSydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, AustraliaSydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, AustraliaSydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, AustraliaUniversity of Technology, Sydney, New South Wales, AustraliaUniversity of Otago, Dunedin, New ZealandAndrology Department, Concord, AustraliaAndrology Department, Concord, AustraliaObjective: Androgen insensitivity syndrome (AIS) due to androgen receptor (AR) mutations creates a spectrum of clinical presentations based on residual AR function with the mildest impairment creating mild AIS (MAIS) whose undefined molecular mechanism and subtle clinical features leave it less understood and underdiagnosed. Design: In silico modeling and in vitro androgen bioassay of the mutated AR are used to identify its structural and physiological mechanism. Clinical features and responses to high-dose testosterone treatment of three cases of MAIS across a six-generation family pedigree are described. Methods: Structural and dynamic in silico molecular modeling and in vitro yeast-based androgen bioassays of the mutant AR are employed. Three cases of MAIS with consistent (gynecomastia and micropenis) and variable (infertility) clinical features across generations are reported, and the effects of high-dose testosterone treatment are studied. Results: The missense AR exon 8 mutation (nucleotide aga → gga, p.R872G arginine to glycine), known to cause an increased ligand dissociation rate in mutant AR in binding assays, was analyzed. Modeling shows that the mutation weakens the closure energy of the ‘lid’ of the ligand-binding pocket, allowing easier ligand dissociation from the binding site but with unimpaired in vitro androgen bioactivity. High-dose testosterone treatment for 3 years in one young man caused increased virilization and height growth but was ineffective for treating micropenis. Genetic counseling allowed effective prediction of MAIS risks in progeny for carrier and noncarrier sisters. Conclusions: The differential diagnosis and clinical management of MAIS is reviewed. The novel molecular mechanism of an AR ligand-binding domain mutation in MAIS may be present in other cases of MAIS.https://ec.bioscientifica.com/view/journals/ec/14/1/EC-24-0567.xmlandrogen insensitivity syndromeandrogen receptorstructural molecular modelingclinical genetics |
| spellingShingle | Ravind Pandher Ruby Chang Yiqun Chang David E Hibbs Jonathan J Du Kristine McGrath Alison Heather Veena Jayadev David J Handelsman Molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndrome Endocrine Connections androgen insensitivity syndrome androgen receptor structural molecular modeling clinical genetics |
| title | Molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndrome |
| title_full | Molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndrome |
| title_fullStr | Molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndrome |
| title_full_unstemmed | Molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndrome |
| title_short | Molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndrome |
| title_sort | molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndrome |
| topic | androgen insensitivity syndrome androgen receptor structural molecular modeling clinical genetics |
| url | https://ec.bioscientifica.com/view/journals/ec/14/1/EC-24-0567.xml |
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