MOLECULAR-PHENOTYPIC CORRELATIONS IN THE ANDROGEN INSENSITIVITY SYNDROME

Abstract

The androgen insensilivity syndrome (AIS) is a classic example of a hormone resistance disorder. In the presence of a 46,XY karyotype and normal or increased androgen levels, affected individuals have a female or ambiguous external genital phenotype, resulting from abnormalities of the intracellular androgon receptor (AR), required to mediate the action of androgens. Using polymerase chain reaction, denaturing gradient gel electrophoresis and dideoxy sequencing, we have identified single nucleolide mutations in the AR gene causing amino acid (AA) substitutions in the AR in 16 AIS subjects (9 complete [CAIS], 7 partial [PAIS]). To determine whether a correlation exists between the specific molecular defect and its clinical expression, we have analyzed these mutations and 70 reported by others, with respect to the location, nature and functional effects of the AA change. The majority (89%) of AA alterations occurred in the steroid-binding domain (SBD), 70% in the central region, encoded by exons E, F and G of the AR gene. Mutations in exons D and E predominantly cause CAIS (CAIS:PAIS-4.4:1). In contrast, mutations in exons F, G and H, encoding the C-terminal region of the SBD, cause CAIS or PAIS with fairly equal frequency (CAIS:PAIS = 1-2:1). This suggests that the region encoded by exons D and E, plays a particularly critical role in AR function. Highly charged residues Arg (basic) and Asp (acidic) are the most frequently altered (57% of CAIS; 44% of PAIS). The phenotype resulting from the AA change appears lo correlate with the severity of the change: conversion of Arg to a markedly different AA, such as Cys, produces the CAIS phenotype, while a conservative change, Arg to His (also a basic AA), is associated with evidence of androgen action in vivo and retention of transactivation capacity by the AR, when analyzed in vitro. A number of sites in the AR gene appear to be mutational “hot spots” (Arg774, Arg855, Val866): although CAIS or PAIS may occur with different mutations at the same site, no single mutation has yet been found that produces CAIS in one kindred and PAIS in another. Analysis of recreated mutant receptors indicates that retention of androgen-dependent transactivation activity in vitro correlates in general with retention of AR function in vivo. These data may enable prediction of likely response to androgen in subjects with mutations causing PAIS.

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