A novel mutation (N233K) in the transactivating domain and the N756S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility*

  title={A novel mutation (N233K) in the transactivating domain and the N756S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility*},
  author={Yvonne Lundberg Giwercman and Andrej Nikoshkov and Birgitta Bystr{\"o}m and {\AA}ke Pousette and Stefan Arver and Anna Wedell},
  journal={Clinical Endocrinology},
OBJECTIVE Resistance to androgens has been suggested as a possible cause of male infertility. This hypothesis is based mainly on binding studies in genital skin fibroblasts but the molecular evidence is sparse. 

A novel mutation in the transactivation-regulating domain of the androgen receptor in a patient with azoospermia.

Molecular analyses may be useful for genetic counseling of candidates with regard to the use of assisted reproductive techniques and might be responsible for some cases of idiopathic infertility, the present study suggested.

Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations

The aim of the study was to analyse the prevalence of AR gene mutations in male infertility and to clarify the genotype‐phenotype relation.

Promoter-Dependent Activity on Androgen Receptor N-Terminal Domain Mutations in Androgen Insensitivity Syndrome

Clinical and experimental analyses have identified novel AR-signalling defects associated with mutations in the structurally disordered AR-NTD domain in patients with AIS.

Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility

Well‐characterized in vitro functional assays can be used for genotype–phenotype correlation; however, for mild forms of AIS, as associated with male infertility, experimental evidence is scarce or lacking and optimal in vitrofunctional tests informative about the genotype-phenotype relation have not been described.

A Novel Mutation in the D-Box of the Androgen Receptor Gene (S597R) in Two Unrelated Individuals Is Associated with both Normal Phenotype and Severe PAIS

The same mutation at this codon can cause significantly different phenotypes as shown by the variation in masculinization of these individuals, with 1 severely affected child and 1 normally developed man.

The contributions of deficient androgen action in spermatogenic disorders.

The role of mutations in the androgen receptor (AR) in idiopathic infertility and, in particular, the contribution of expanded cytosine-adenine-guanine (CAG) repeats in exon 1 of the AR gene to the occurrence of male idiopATHic infertility is highlighted.

Role of conserved hydrophobic amino acids in androgen receptor AF-1 function.

It is concluded that conserved hydrophobic residues are important for receptor-dependent gene transcription and that M244, L246 and V248 are part of the binding interface for TFIIF.

Bridging structural biology and genetics by computational methods: An investigation into how the R774C mutation in the AR gene can result in complete androgen insensitivity syndrome

The results therefore strongly support the biochemical data, e.g., the mutants' inability to form AR‐ligand complexes at 37°C and its characteristic reversible thermolability, clearly indicating the value of such computational methods.

No association between mutations in the human androgen receptor GGN repeat and inter-sex conditions.

Findings indicate that point mutations in the GGN repeat are frequently found in the general male population, but are usually not associated with profound changes in the male phenotype.



Azoospermia associated with a mutation in the ligand-binding domain of an androgen receptor displaying normal ligand binding, but defective trans-activation.

Genetic screening in subjects with defective spermatogenesis and in 110 fertile controls identified an azoospermic patient with an amino acid substitution (Gln-->Glu) in residue 798 of the AR gene, which caused a subtle, but significant, decrease in receptor trans-activation function in vitro that is consistent with the phenotype.

Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation.

The findings suggest that domains important to the in vivo function of the receptor reside within the amino terminus and that disruption of these domains can occur with only subtle effects on receptor binding.

The AF1 and AF2 Domains of the Androgen Receptor Interact with Distinct Regions of SRC1

It is demonstrated that p160 coactivators such as SRC1 (steroid receptor coactivator 1) interact directly with the N terminus in a ligand-independent manner via a conserved glutamine-rich region between residues 1053 and 1123.

Delineation of Two Distinct Type 1 Activation Functions in the Androgen Receptor Amino-terminal Domain*

Results showed that neither AF-1a norAF-1b was required for AP-1 trans-repression, demonstrating that AR-mediated trans- repression and trans-activation are discrete functions.

The clinical and molecular spectrum of androgen insensitivity syndromes.

It is concluded that mutations in the androgen receptor gene may be present throughout the whole coding region and provided evidence that several mutational hot spots exist.

Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility.

The data indicate a direct relation between length of the AR polyglutamine tract and the risk of defective spermatogenesis that is attributable to the decreased functional competence of AR with longer glutamine tracts.

The Linkage of Kennedy’s Neuron Disease to ARA24, the First Identified Androgen Receptor Polyglutamine Region-associated Coactivator*

The identification of a nuclear G-protein, Ras-related nuclear protein/ARA24, as the first AR coactivator that can bind differentially with different lengths of poly-Q within AR is reported, suggesting poor interaction and weaker coactivation of ARA24 to the longerpoly-Q AR in the X-linked spinal and bulbar muscular atrophied AR could contribute to the weaker transactivation of AR.

Identification of Two Transcription Activation Units in the N-terminal Domain of the Human Androgen Receptor (*)

The data presented show that the size and location of the active TAU in the human AR is variable, being dependent on the promoter context and the presence or absence of the ligand binding domain.