Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene

  title={Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene},
  author={Gernot H. G. Sinnecker and Olaf Hiort and Esther M. Nitsche and P. M. Holterhus and Klaus Kruse and German Neuromonitoring Study Group},
  journal={European Journal of Pediatrics},
Abstract In the genetic male, mutations of the androgen receptor (AR) gene cause phenotypes ranging from female to subfertile male. Binding assays on genital skin fibroblasts and DNA analysis alone provide incomplete information about receptor function. We used the sex hormone-binding globulin (SHBG) response to stanozolol as a measure of AR function and correlated the results with phenotypes which were classified according to the degree of defective masculinization. Of the 34 patients… 

Phenotypic Heterogeneity Associated with Identical Mutations in Residue 870 of the Androgen Receptor

P phenotypic heterogeneity associated to identical mutations in the AR gene is probably due to individual functional differences in AR coregulator molecules, and this results in an AIS characterized by bilateral gynecomastia, normal male external genitalia, and normal sperm counts.

In-vitro Characterization of Androgen Receptor Mutations Associated with Complete Androgen Insensitivity Syndrome Reveals Distinct Functional Deficits

It is concluded that mutations in the AR have to be characterized meticulously, not only to prove any quantitative functional deficit as a proof of consequence, but also to gain knowledge on qualitative functional properties.

Investigation of androgen receptor gene mutations in a series of 21 patients with 46,XY disorders of sex development

This study investigates AR gene mutations in 46,XY DSD patients with normal testosterone secretion, either normal or high testosterone/dihydrotestosterone (T/DHT) ratio and normal SRD5A2 gene analysis, collectively, suggestive of androgen insensitivity syndrome (AIS).

A Novel Point Mutation in the Hormone Binding Domain of the Androgen Receptor Associated with Partial and Minimal Androgen Insensitivity Syndrome

It is concluded that phenotypic variations in mild AR defects are striking and can remain undetected even until late in life.

Molecular features and clinical phenotypes in androgen insensitivity syndrome in the absence and presence of androgen receptor gene mutations

Patients with clinically evident complete androgen insensitivity syndrome are likely to harbor an AR gene mutation, demanding that the two polymorphic regions must always be included in molecular analyses of the AR gene.

Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.

Somatic mosaicism of the AR gene can represent a substantial factor for the individual phenotype by shifting it to a higher degree of virilization than expected from the genotype of the mutant allele alone.

Novel molecular defects in the androgen receptor gene of Mexican patients with androgen insensitivity

The view that nonsense mutations in the AR results almost invariably in a CAIS phenotype and underly the importance of the steroid‐binding domain (SBD) for the AR functional activity is reaffirmed.

Expression of two functionally different androgen receptors in a patient with androgen insensitivity

The present case clearly demonstrates the molecular mechanism by which somatic mosaicism of the androgen receptor gene can modulate in vivo androgen action and underlines the importance of particular notice on somatic mosaicicism in all androgen insensitivity syndrome patients carrying de novo mutations of the AR gene.

The Molecular Basis of Androgen Insensitivity

Androgen insensitivity syndrome (AIS) as the clinical entity of defective androgen action with variable phenotypes in 46,XY patients is caused by mutations of the X-chromosomal AR gene.

Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5alpha dihydrotestosterone availability.

The distinct phenotypic variation in AIS here is explained by differences in the availability of 5alpha-dihydrotestosterone during embryonic sex differentiation.



Characterization of mutant androgen receptors causing partial androgen insensitivity syndrome.

The results demonstrate the clinical, functional, and molecular heterogeneity in the syndrome of partial androgen insensitivity.

Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome.

The results suggest that mutations affecting the ligand binding domain of the androgen receptor are the most frequent cause of AIS, although some cases of PAIS may be the result of other, as yet undefined, genetic lesions.

Detection of point mutations in the androgen receptor gene using non-isotopic single strand conformation polymorphism analysis. German Collaborative Intersex Study Group.

An improved non-radioactive single strand polymorphism analysis is reported for rapid detection of androgen receptor gene mutations in affected individuals and indicates that the omission of radioisotopes is advantageous in a clinical setting.

Single strand conformation polymorphism analysis of androgen receptor gene mutations in patients with androgen insensitivity syndromes: application for diagnosis, genetic counseling, and therapy.

The data show that new mutations may occur in the androgen receptor gene leading to sporadic androgen insensitivity syndrome, and molecular genetic characterization of the variant allele can serve as a primary tool for diagnosis and subsequent therapy.

Mutations in the ligand-binding domain of the androgen receptor gene cluster in two regions of the gene.

The nucleotide sequence of the androgen receptor is analyzed from 22 unrelated subjects with substitution mutations of the hormone-binding domain that included individuals with the phenotype of complete testicular feminization, four had incomplete testicularfeminization, and seven had Reifenstein syndrome.

Complete androgen insensitivity due to deletion of exon C of the androgen receptor gene highlights the functional importance of the second zinc finger of the androgen receptor in vivo.

In a pair of siblings with complete androgen insensitivity who had supranormal levels of androgen binding in genital skin fibroblasts, polymerase chain reaction and Southern blot analysis of the androgen receptor gene revealed an in-frame deletion of exon C encoding the second zinc finger of the receptor.

Phenotypic variation and detection of carrier status in the partial androgen insensitivity syndrome.

P phenotypic variation in families affected by partial androgen insensitivity is dependent on factors other than abnormalities of the androgen receptor gene alone, and the severity of genital abnormalities in an affected offspring cannot be reliably predicted.

Complete androgen insensitivity syndrome characterized by increased concentration of a normal androgen receptor in genital skin fibroblasts.

  • I. HughesB. Evans
  • Biology, Medicine
    The Journal of clinical endocrinology and metabolism
  • 1986
A new variant of CAIS is described which is characterized by an increased concentration of androgen receptors that appear to be quantitatively and qualitatively normal.


Treatment seems to be indicated in certain patients with partial androgen insensitivity, in particular in patients with the Val → Leu substitution in codon 866 of the hormone-binding domain of the androgen receptor.

Androgen insensitivity in forty-nine patients: classification based on clinical and androgen receptor phenotypes.

The gene coding for the androgen receptor in patients with androgen insensitivity syndrome appears intact, and only 3 receptor-positive AIS cell strains of 30 studied failed to show an increase in specific receptor binding after prolonged androgen exposure in vitro.