Molecular Analysis of Human Androgen Receptor Mutations Causing Motor Neuronopathy or Infertility
| Author | Abdullah, Abdullah A. Rasool | |
|---|---|---|
| metadata.dc.contributor.department | McGill University, Department of Biology | |
| metadata.dc.date.accessioned | 2026-09-20T15:53:20Z | |
| Publication date | 1997 | |
| Degree level | Doctoral | |
| Abstract | Abstract : hAR mutations cause, or predispose to, androgen insensitivity syndrome (AIS), spinobulbar muscular atrophy (SBMA, a motor neuronodegenerative disease), and prostate cancer. I investigated the pathogenic mechanism of three AR mutations: expansion of the trinucleotide repeat (CAG)n coding for the polymorphic polyglutamine (polyGln) tract in exon 1 of the AR, which causes SBMA, and mutations in exon 5 (Asn727Lys) and exon 8 (Met886Val) of the AR ligand-binding domain (LBD), each of which causes oligospermic infertility. In the transiently transfected motor neuron hybrid cell line (NSC34), the polyGln-expanded AR is ∼40% less transactive than the wild-type receptor despite a higher AR protein content. The polyGln-expanded AR has normal androgen-binding kinetics. A polyGln-expanded AR made from mixed CAG and CAA codons is also hypotransactive, suggesting protein dysfunction. The polyGln-expanded AR is more resistant than normal to short, cell-free trypsinolysis and yields a distinct set of Gln-expanded fragments even after extended exposure with a denaturant, suggesting conformational changes. COS cells transfected with (CAG)- or (CAG/CAA)-expanded AR cDNA generate a unique 75 kDa fragment containing the Gln tract and are twice as likely to die apoptotically. Androgen caused a negative shift in the voltage-dependence of activation, resulting in an increase in the T-type Ca2+-channel window current in two motor neuron cell lines expressing polyGln-expanded AR Accumulation of an aberrant or protease-resistant polyGln-expanded AR firument may be the proximate motor neuronopathic agent in SBMA. This agent may cause Ca2+ overload and motor-neuron apoptosis in SBMA by abnormal activation of voltage-gated Ca2+ channels Neither the Met886Val nor the Asn727Lys mutation affects androgen binding in genital skin fibroblasts or transfected COS cells. However, both reduce transactivation by ~40%, a result paralleled by A-R binding to a steroid response element. To my knowledge, these are the first AR LBD mutations that impair DNA binding. Mesterolone normalized spermatogenesis in Asn727Lys subjects. Interestingly, the Asn727Lys AR is 50% hypertransactive with mesterolone at 37°C but not at 34°C, and trypsinolysis indicates that it is conformationally normal with mesterolone but not with 5α-DHT | |
| metadata.dc.identifier.other | Drupal node 4379 | |
| metadata.dc.identifier.other | https://digitalrepository.uob.edu.bh/en/dar/molecular-analysis-human-androgen-receptor-mutations-causing-motor-neuronopathy-or-infertility | |
| metadata.dc.identifier.uri | http://165.227.56.122/handle/123456789/7417 | |
| Language | en | |
| Link | https://digitalrepository.uob.edu.bh/en/_flysystem/fedora/2025-08/001764_molecular_analysis_of_human_androgen_receptor_mutations_causing_motor_neuronopathy_or_infertility.pdf | |
| Subject | Molecular Biology--Dissertations | |
| Subject | Biochemistry--Dissertations | |
| Subject | Human reproduction--Molecular aspects--Dissertations | |
| Subject | Physiology--Dissertations | |
| Title | Molecular Analysis of Human Androgen Receptor Mutations Causing Motor Neuronopathy or Infertility | |
| Type | Doctoral Dissertation | |
| College | College of Science | |
| Department | Biology |
Files
Original bundle
1 - 1 of 1
Loading...
- Name:
- node-4379-1-001764_molecular_analysis_of_human_androgen_receptor_mutations_causing_motor_neuronopathy_or_infertility.pdf
- Size:
- 10.67 MB
- Format:
- Adobe Portable Document Format