Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males

Abstract

The androgen receptor (AR) is essential to the normal development of the male internal and external genitalia. Consequently, impairment of AR function can result in undermasculinized genitalia that vary from a completely female appearance to isolated hypospadias. Since in vitro studies demonstrate that AR function is reduced by expansion of the polyglutamine tract within the receptor [AR(Gln)(n)]; this study examined whether longer AR(Gln)(n) repeats are associated with moderate to severe undermasculinization. The average AR(Gln)(n) length of the undermasculinized group (n = 78, median 25, interquartile range 23-26) was significantly greater than that of the control population (n = 850, median 23, inter-quartile range 22-26, P = 0.002). The odds ratio of having >/=23 repeats (as opposed to </=22 repeats) in the undermasculinized group was 2.51 (95% confidence interval 1.41-4.48). The estimated increase in the OR for each additional repeat was 9.07%. Hormonal and AR binding data were used to select subgroups of patients that had a reduced likelihood of a sex steroid biosynthetic defect or an AR abnormality. A clear trend was demonstrated in which the mean AR(Gln)(n) length and the odds ratio increased with the rigour of the subgroup selection criteria. Undermasculinization of the male genitalia is a rare example of a non-neurodegenerative, congenital disorder that is associated with triplet repeat allele size. Furthermore, the association of both undermasculinized genitalia and isolated male factor infertility with AR(Gln)(n) length provides additional evidence that they may represent different degrees of severity of the same disease process.

Hypospadias: Interactions between environment and genetics

“…The role of amplification of the CAG repeats remains to be determined [113] and may be associated with undermasculinized genitalia, including hypospadias [114]. For some authors, the V89L variant of the SRD5A2 gene is a risk factor for hypospadias [115], whereas for others it is not [116].…”

Evidence that luteinising hormone receptor polymorphisms may contribute to male undermasculinisation

“…Control individuals ðn ¼ 55Þ who had either a characterised AR mutation or a diagnosis of Denys -Drash syndrome (as opposed to the undermasculinised group without an identifiable cause) were selected from the same database. The validity of using this control group is supported by the previous demonstration that the distribution of AR(Q)n lengths (which has geographic and ethnic variation) within this group is the same as that in the normal population (8). Local ethics committee approval was obtained for the use of patient samples as part of a sexual development disorders program.…”

“…However, a subset of these cases of undermasculinisation without an apparent cause have an increased number of glutamines (but within the normal range of 11 -31 repeats) within the AR polymorphic polyglutamine tract (AR(Q)n ) compared with cases with AR mutations and the normal population (8,9). It is probable that polymorphisms in other factors involved in androgen action and production, such as the LHR, can also contribute to the multi-factorial aetiology of undermasculinisation (10).…”

Genetic evidence to exclude the androgen receptor-polyglutamine associated coactivator, ARA-24, as a cause of male undermasculinisation

“…Excessively long AR[Gln] n tracts (40 -62 repeats) occur in the rare X-linked spinal and bulbar muscular atrophy (SBMA), which often has the associated features of male infertility, testicular atrophy and gynaecomastia (5). Smaller increases in polyglutamine repeat length (remaining within the normal range) may contribute to moderate to severe undermasculinised male genitalia (6). In the latter disorder, AR[Gln] n length is clearly affecting at least one other factor that is sensitive to its length and is therefore probably interacting directly with this region of the AR.…”

“…Furthermore, all patients had AR-binding studies performed on genital skin fibroblasts and all had normal receptor androgen affinity and binding capacity (1) as measured using methods described previously (11). AR[Gln] n was determined as described previously (6) or by direct sequencing.…”