| Research Abstract |
We found a patient who was diagnosed phenotypically and endocrinologically as having complete androgen insensitivity syndrome (AIS), but who had no abnormality in the androgen receptor (AR) gene. Transactivation by the normal entire AR in the patient fibroblasts was markedly low compared with that in the controls, strongly suggesting that this patient manifests AIS due to the abnormality of coactivator. The aims of the present study were the establishment of the concept of a coactivator disease and the isolation of its coactivator, and the following results were obtained. Investigation of the transactivation by the AR, glucocorticoid receptor (GR), their AF-1- or AF-2-truncated receptors and their chimeric receptors in primary-cultured genital skin fibroblasts from the patient revealed that transmission of the activation signal from AF-1 of the AR was disrupted. Co-transfection of known transcriptional cofactors did not restore the impaired AR-dependent transactivation in the patient. The binding of a protein with an apparent Mr of about 90 kDa to GST-fused AF-1 of the AR was lost in the patient fibroblasts. A cDNA which enhances the AR-dependent transactivation was isolated by yeast two hybrid system using as AR-AF-1 as a bait.
In conclusion, we have established a new form of steroid hormone insensitivity, a coactivator disease, and also isolated one of the AR-AF-1-specific coactivators.
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