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THE ANDROGEN RECEPTOR GGN POLYMORPHISM. Genetic and functional analyses.

Lundin, Kristina LU (2007) In Lund University Faculty of Medicine Doctoral Dissertation Series 2007:131.
Abstract
Male sex development and reproductive function is regulated by androgens acting via the androgen receptor (AR). The AR harbours two polymorphic repeats of CAG and GGN triplets, encoding glutamines and glycines, respectively. Both polymorphisms affect the AR transactivation ability, although the function of the GGN repeat was virtually unknown at the start of this project. Thus, the main purpose with this thesis was to study the in vivo and in vitro impact of GGN repeat variation on AR function. A reliable method for studying the segment was established, after which the GGN repeat was studied in normal men, and in men with androgen-related disorders such as prostate cancer, testicular cancer, infertility, cryptorchidism, and hypospadias.... (More)
Male sex development and reproductive function is regulated by androgens acting via the androgen receptor (AR). The AR harbours two polymorphic repeats of CAG and GGN triplets, encoding glutamines and glycines, respectively. Both polymorphisms affect the AR transactivation ability, although the function of the GGN repeat was virtually unknown at the start of this project. Thus, the main purpose with this thesis was to study the in vivo and in vitro impact of GGN repeat variation on AR function. A reliable method for studying the segment was established, after which the GGN repeat was studied in normal men, and in men with androgen-related disorders such as prostate cancer, testicular cancer, infertility, cryptorchidism, and hypospadias. Two predominant alleles of 23 and 24 GGN repeats, respectively, were found in all subject categories studied. GGN23 was the most common allele in all men except cryptorchid men and boys with penile hypospadias, in whom GGN24 was predominant. Point mutations within the GGN repeat were present in ~1% of the Swedish population, and were not associated with severe genital malformations. In normal men, GGN<23 was associated with a decrease in semen volume compared to GGN?23. Expression vectors harbouring the AR cDNA with GGN10, 23, 24, or 27, in combination with the median CAG repeat length, were constructed and tested in an in vitro expression system. Cos-1 cells were transiently transfected with vectors containing the GGN constructs, the prostate specific antigen promoter in combination with the Luciferase reporter gene, and ?-galactosidase gene. Cells were grown in the presence of 0, 0.1, 1.0, 10 and 100 nM of 5?-dihydrotestosterone or R1881. Western blot analysis was performed to assess the amount of androgen receptor protein. The in vitro results indicated a functional difference between the two predominant alleles, with GGN23 being superior in function. A non-linear association between GGN repeat length and AR transcriptional function was seen. No differences in AR protein levels for the different GGN repeat lengths were seen. The mode of inheritance for the CAG and GGN repeats was assessed by single nucleotide polymorphism analysis. Linkage disequilibrium was observed between the CAG and GGN repeats, with long GGN repeats being inherited together with short CAG repeats, and vice versa.



Thus, in this thesis I have shown that the AR gene GGN repeat plays an important role in normal male sex development and male reproductive function. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Gromoll, Jörg, Institute of Reproductive Medicine, University of Munster, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Medicine (human and vertebrates), Functional domain, Genetic predisposition, Reproductive function, Sex hormone, Transactivation function, Repeat, Polymorphism, Androgen receptor, Transcription factor, Medicin (människa och djur), Endocrinology, secreting systems, diabetology, Endokrinologi, sekretion, diabetologi
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2007:131
pages
128 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Lilla aulan UMAS, entrance 59 Malmö
defense date
2007-11-09 09:15:00
ISSN
1652-8220
ISBN
978-91-85897-09-4
language
English
LU publication?
yes
additional info
KB Lundin, A Giwercman, J Richthoff, P-A Abrahamsson and YL Giwercman. 2003. No association between mutations in the human androgen receptor GGN repeat and inter-sex conditions. Molecular Human Reproduction, vol 9 pp 375-379.
EL Aschim, A Nordenskjöld, A Giwercman, KB Lundin, Y Ruhayel, TB Haugen, T Grotmol and YL Giwercman. 2004. Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene. The Journal of Clinical Endocrinology & Metabolism, vol 89 pp 5105-5109.
KB Lundin, YL Giwercman, L Rylander, L Hagmar and A Giwercman. 2006. Androgen receptor gene GGN repeat length and reproductive characteristics in young Swedish men. European Journal of Endocrinology, vol 155 pp 347-354.
KB Lundin, A Nordenskjöld, A Giwercman and YL Giwercman. 2006. Frequent finding of the androgen receptor A645D variant in normal population. The Journal of Clinical Endocrinology & Metabolism, vol 91 pp 3228-3231.
KB Lundin, A Giwercman, N Dizeyi and YL Giwercman. 2007. Functional in vitro characterisation of the androgen receptor GGN polymorphism. Molecular and Cellular Endocrinology, vol 264 pp 184-187.
id
b33cbabd-fe54-42c5-ae96-6dcd71a0649d (old id 599145)
date added to LUP
2016-04-01 16:31:00
date last changed
2019-05-22 06:06:31
@phdthesis{b33cbabd-fe54-42c5-ae96-6dcd71a0649d,
  abstract     = {{Male sex development and reproductive function is regulated by androgens acting via the androgen receptor (AR). The AR harbours two polymorphic repeats of CAG and GGN triplets, encoding glutamines and glycines, respectively. Both polymorphisms affect the AR transactivation ability, although the function of the GGN repeat was virtually unknown at the start of this project. Thus, the main purpose with this thesis was to study the in vivo and in vitro impact of GGN repeat variation on AR function. A reliable method for studying the segment was established, after which the GGN repeat was studied in normal men, and in men with androgen-related disorders such as prostate cancer, testicular cancer, infertility, cryptorchidism, and hypospadias. Two predominant alleles of 23 and 24 GGN repeats, respectively, were found in all subject categories studied. GGN23 was the most common allele in all men except cryptorchid men and boys with penile hypospadias, in whom GGN24 was predominant. Point mutations within the GGN repeat were present in ~1% of the Swedish population, and were not associated with severe genital malformations. In normal men, GGN&lt;23 was associated with a decrease in semen volume compared to GGN?23. Expression vectors harbouring the AR cDNA with GGN10, 23, 24, or 27, in combination with the median CAG repeat length, were constructed and tested in an in vitro expression system. Cos-1 cells were transiently transfected with vectors containing the GGN constructs, the prostate specific antigen promoter in combination with the Luciferase reporter gene, and ?-galactosidase gene. Cells were grown in the presence of 0, 0.1, 1.0, 10 and 100 nM of 5?-dihydrotestosterone or R1881. Western blot analysis was performed to assess the amount of androgen receptor protein. The in vitro results indicated a functional difference between the two predominant alleles, with GGN23 being superior in function. A non-linear association between GGN repeat length and AR transcriptional function was seen. No differences in AR protein levels for the different GGN repeat lengths were seen. The mode of inheritance for the CAG and GGN repeats was assessed by single nucleotide polymorphism analysis. Linkage disequilibrium was observed between the CAG and GGN repeats, with long GGN repeats being inherited together with short CAG repeats, and vice versa.<br/><br>
<br/><br>
Thus, in this thesis I have shown that the AR gene GGN repeat plays an important role in normal male sex development and male reproductive function.}},
  author       = {{Lundin, Kristina}},
  isbn         = {{978-91-85897-09-4}},
  issn         = {{1652-8220}},
  keywords     = {{Medicine (human and vertebrates); Functional domain; Genetic predisposition; Reproductive function; Sex hormone; Transactivation function; Repeat; Polymorphism; Androgen receptor; Transcription factor; Medicin (människa och djur); Endocrinology; secreting systems; diabetology; Endokrinologi; sekretion; diabetologi}},
  language     = {{eng}},
  publisher    = {{Department of Clinical Sciences, Lund University}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{THE ANDROGEN RECEPTOR GGN POLYMORPHISM. Genetic and functional analyses.}},
  volume       = {{2007:131}},
  year         = {{2007}},
}