Molecular genetic heterogeneity of androgen receptor gene mutations in human androgen insensitivity syndromes

Androgen receptors (AR) bind testosterone and dihydrotestosterone to form transacting transcriptional regulatory complexes necessary for induction of specific genes during normal male sex differentiation and development and in maintenance of normal male physiology. The androgen insensitivity syndrome (AIS) is an X chromosome-linked disorder, resulting from the impairment of the biological actions of androgenic hormones related to defects in the intracellular AR. Therefore, the clinical syndromes of androgen insensitivity provide a human model for understanding the mechanisms of androgen action and the molecular lesions that lead to abnormalities of male sex differentiation. The recent isolation and cloning of the human AR cDNA provides molecular probes for investigating AR gene structure and function in AIS. In the complete form of AIS, affected subjects present with completely female external genitalia, but with a short vagina and absent Mullerian ducts; with normal-size testes located in the abdominal or inguinal area, but with hypoplastic Wolffian ducts; with normal female secondary-sex characteristics at puberty, but usually sparse or absent pubic and body hair. In adults, serum testosterone and LH concentrations are at or above the normal male adult range. Determination of androgen receptor binding in cultured genital skin fibroblasts has demonstrated the genetic heterogeneity of complete AIS, some patients having undetectable binding, or the so-called receptor (-) form whereas others have quantitatively normal binding, termed the receptor (+) form. Radiolabeled cDNA probes that span various parts of the AR gene, including the entire steroid-binding domain and the DNA-binding domain, as well as part of the 5' region of the gene were used to screen for AR mutations on Southern blots prepared by restriction endonuclease digestion of genomic DNA from human subjects with complete AIS. In three unrelated subjects with the receptor (-) form of complete AIS, a deletion of the AR gene involving the steroid-binding domain was detected. In another affected subject, a deletion in the 5' portion of the AR gene was identified. However, in other subjects with complete AIS no gross gene mutation was detected on Southern blots.