ACTION OF HORMONES ON PROTEIN AND RNA METABOLISM

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Defects in the androgen receptor (AR) cause a spectrum of phenotypic abnormalities ranging from complete androgen resistance (complete testicular feminization), to partial forms of androgen resistance (such as Reifenstein syndrome), to individuals with evidence of undervirilization or infertility. To date, much of the information regarding AR defects has come from studies of patients with the most severely affected phenotypes or from individuals with clearcut abnormalities of androgen binding. Much less is known regarding the defects causing the less severe phenotypic abnormalities and, with the exception of mutations in the DNA-binding domain, virtually nothing is known of the mechanisms by which large or small changes of receptor structure are translated into abnormalities of AR function. We propose to conduct experiments in three related areas: 1) The AR defect will be defined in two groups: one phenotypic (partial forms of androgen resistance) and one based on categorization by ligand-binding assays (normal or reduced levels of qualitatively normal ligand binding); 2) Identify proteins that interact with functionally important segments of the AR. These experiments will include studies to demonstrate that the interactions occur in cells and that the proteins identified modulate AR function; 3) Conduct studies to correlate alterations of AR structure [deletions within the AR or amino acid substitutions in the hormone- binding domain (HBD)] with the capacity of the AR to bind to DNA, undergo posttranslational modifications and bind specific interacting proteins. The results of these studies will further define the AR gene mutations that can cause defects of virilization (particularly as it pertains to less severely affected phenotypes) and will provide the first detailed information regarding the mechanism(s) by which mutations in the AR (amino terminal deletions, amino acid substitutions in the HBD) cause defects of AR function.