| Summary: | Two previously identified sequence alterations in the androgen receptor gene of patients with complete androgen resistance are studied to prove their pathogenicity. Family studies confirm that the mutation segregates with the phenotype and that the mothers are heterozygous carriers. In one family a sibling of the patient is identified as a heterozygous carrier. Mutant cDNAs encoding the mutant receptors are constructed and expressed in COS-1 cells. The resulting mutant receptors show a decreased apparent equilibrium constant for androgens, faster dissociation rates and impaired transactivation. Further studies reveal that both mutant receptors were either inactivated or destroyed in the presence of hormone, while the normal receptor is stabilized and up-regulated by incubation with ligand. These results prove that the sequence alterations thus identified are pathogenic and illustrate a dual mechanism of pathogenicity: an affinity defect combined with a loss of binding activity in the presence of hormone, resulting in receptors incapable of supporting normal male sexual development.
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