Review
Molecular biology of androgen insensitivity

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Abstract

Androgen insensitivity syndrome (AIS) is the most common specific cause of 46,XY disorder in sex development. The androgen signaling pathway is complex but so far, the only gene linked with AIS is the androgen receptor (AR). Mutations in the AR are found in most subjects with complete AIS but in partial AIS, the rate has varied 28–73%, depending on the case selection. More than 400 different mutations in AR leading to AIS have been reported. Most mutations are missense substitutions located in the ligand binding domain of the receptor. However, when systematically screened, a substantial amount of mutations can be detected also in the N-terminal domain encoded by exon 1. Within this exon lie two trinucleotide, CAG and GGN repeat regions which are polymorphic in length. Their role in androgen insensitivity is somewhat unclear. Recent advances in protein modeling have resulted in better understanding of the mechanism of known AR mutations.

Section snippets

Androgen insensitivity syndrome

Target tissue resistance to androgens, testosterone (T) and its 5α-reduced product dihydrotestosterone (DHT), leads to androgen insensitivity syndrome (Hughes and Deeb, 2006). Hormone resistance is diagnosed when serum hormone concentrations are normal or high but the clinical effect is subnormal. In addition to androgens, steroid hormone resistance states have been reported for other steroid hormones including glucocorticoids (Vingerhoeds et al., 1976), mineralocorticoids (Fernandes-Rosa et

Structure and function of the androgen receptor protein and gene

The AR is a member of the steroid and nuclear receptor superfamily which also includes mineralocorticoid, glucocorticoid, estrogen and progesterone receptors. These receptors are grouped as class I receptors of the larger nuclear receptor superfamily, which includes thyroid hormone receptors, retinoic acid receptors, peroxisome proliferator-activated receptors and vitamin D receptors (Bennett et al., 2010).

The unliganded AR lies in the cell cytoplasm and is associated in complex with heat shock

46,XY sex development and differentiation

The early steps of 46,XY sex development – formation of the bipotential gonad and its differentiation into the testis – are not dependent on androgen action (Mendonca et al., 2009). The expression of nuclear receptor subfamily 5, group A, member 1 (NR5A1), wingless-type mouse mammary tumor virus integration site member 4 (WNT4), and Wilms’ tumor suppressor gene (WT1) in the urogenital ridge are necessary for the development of the bipotential gonad (MacLaughlin and Donahoe, 2004). In a 46,XY

Phenotypic variation in AIS

The clinical manifestations of androgen resistance vary from external genitalia that are completely female to degrees of partial masculinization (Quigley et al., 1995, Hughes and Deeb, 2006). Though there is a continuum of phenotypic severity, AIS can be divided into three phenotypic forms: complete AIS (CAIS), partial AIS (PAIS), and mild AIS (MAIS).

In a 46,XY individual with AIS, testicular differentiation occurs normally, and immature germ cells are present in the testes at birth and during

AR mutations in AIS

As a rule, a mutation in AR should be found in AIS. However, the rates of detected mutations in AIS vary, depending on AIS phenotype, family history, patient evaluation, and screening method (Audi et al., 2010, Ahmed et al., 2000, Melo et al., 2003). In the largest reported AIS cohort, an AR mutation could be detected in 83% of the cases with CAIS. On the other hand, in PAIS, the mutation detection rate was only 28% (Ahmed et al., 2000). In a recent Brazilian study on 32 AIS patients from 20

AR CAG/GGN repeat polymorphisms and relative androgen insensitivity

There is a polymorphic AR trinucleotide CAG repeat segment encoding a polyglutamine tract in the NH2-terminal domain of the AR (Lubahn et al., 1988, Chang et al., 1988). The length of this repeat region varies from nine to 36 in normal population (Andrew et al., 1997). When this region is ⩾38 repeats in length, it may lead to reduced virilization, defective spermatogenesis and spinal bulbar muscular atrophy (SBMA), known also as Kennedy’s disease (La Spada et al., 1991).

Downstream of the CAG

AR mutation negative AIS

There are some individuals with all in vivo and in vitro features of AIS but in whom no mutation within the AR coding region can be found (Holterhus et al., 2005). In theory, the mutation could lie in the AR promoter region, but such mutation has not been reported. There could also be a coactivator defect. New et al. reported two sisters who were resistant to several steroids, including androgens (New et al., 2001). Also, one subject with CAIS has been reported, in whom the transmission of the

Genetic counselling

AIS is a heritable disorder with significant consequences, thus genetic counselling should be offered to the families of affected individuals. The AR is encoded by an X-chromosomal gene and AIS follows an X-linked recessive pattern of inheritance (Lubahn et al., 1988, Chang et al., 1988). Thus, for any carrier female, there is a 1:2 chance of a child with 46,XY karyotype being affected, and a 1:2 chance of a 46,XX child being a carrier. However, in 30% of cases the mutation arises

Conclusions and future perspectives

More than 400 different mutations in the AR gene have been associated with AIS. Most of these mutations are missense mutations and most mutations affect the ligand-binding domain of the AR. Recently, many novel exon 1 mutations have been reported and it is likely that if this exon is systematically screened for mutations, the rate will further increase.

Whereas a mutation in the AR gene can be found in most, though not all, patients with complete AIS, partial AIS remains a diagnostic challenge:

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