The Androgen receptor (AR) gene is located on chromosome Xq12 and is involved in the generation of the male internal and external genitalia through the actions of testosterone and 5α-dihydrotestosterone (DHT) . The product of this gene belongs to the nuclear receptor class, and is expressed in the developing human penis and urethra . It affects the expression of androgen regulated genes critical for the development of the male sexual phenotype by recognizing the canonical androgen response elements (AREs) in the DNA once it has formed a complex with DHT or testosterone in the cytoplasm .
Mutations in the AR gene that severely impact the function of the receptor can cause the syndrome of partial or complete androgen insensitivity, and have also been observed in a few cases of isolated hypospadias [4–10]. The malformation of hypospadias is described as a birth defect of the urethra in males, and is considered to be a milder form of 46,XY disorder of sex development (DSD). It is characterized by a ventrally placed urinary opening in boys and affects 3 per 1000 males in Sweden since the beginning of the 1970s (data from the annual Swedish Malformation Registry). This disease is influenced both by genes and environmental factors, and about 10 % of these boys have a family history of hypospadias. Most cases with hypospadias are reported to be sporadic .
Hypospadias is usually diagnosed during physical examination of the newborns, with subsequent surgery in their first two years of life. Still, the molecular mechanisms behind this disease, particularly in the sporadic form, are largely unknown.
Since AR mediates important biological effect of testosterone and DHT, it is an obvious candidate in the development of hypospadias. Moreover, greater number of CAG repeats within the AR gene results in longer polyglutamine tracts in the AR, and cause the AR to have a reduced transcriptional activity and to associate with moderate to severe undermasculinized genitalia in XY males . In addition, we previously performed a study in which we , and another independent group , assessed the CAG repeat length in a small number of cases with hypospadias. However, no association was found between the CAG repeat length and the investigated cases when compared to the controls. In the present study, we decided to investigate possible association of the CAG repeat length in the AR gene with the disease of hypospadias in a significantly larger patient material.