PubMed · 14426398
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N NEIMANN, M PIERSON, J LESURE, B PIERSON. [Feminizing testicle].. https://pubmed.ncbi.nlm.nih.gov/14426398/
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Here we report that mutations within the DNA-binding domain of AR, shown previously to inhibit nuclear export to the cytoplasm, cause an androgen-dependent defect in intranuclear trafficking of AR. Mutation of two conserved phenylalanines within the DNA recognition helix (F582, 583A) results in androgen-dependent arrest of AR in multiple subnuclear foci. A point mutation in one of the conserved phenylalanines (DeltaF582, F582Y) is known to cause androgen insensitivity syndrome (AIS). Both AIS mutants (DeltaF582, F582Y) and the export mutant (F582, 583A) displayed androgen-dependent arrest in foci, and all three mutants promoted androgen-dependent accumulation of the histone acetyl transferase CREB binding protein (CBP) in the foci. The foci correspond to a subnuclear compartment that is highly enriched for the steroid receptor coactivator glucocorticoid receptor-interacting protein (GRIP)-1. Agonist-bound wild-type AR induces the redistribution of GRIP-1 from foci to the nucleoplasm. This likely reflects a direct interaction between these proteins because mutation of a conserved residue within the major coactivator binding site on AR (K720A) inhibits AR-dependent dissociation of GRIP-1 from foci. GRIP-1 also remains foci-associated in the presence of agonist-bound F582, 583A, DeltaF582, or F582Y forms of AR. Two-dimensional phospho-peptide mapping and analysis with a phospho-specific antibody revealed that mutant forms of AR that arrest in the subnuclear foci are hypophosphorylated at Ser81, a site that normally undergoes androgen-dependent phosphorylation. Our working model is that the subnuclear foci are sites where AR undergoes ligand-dependent engagement with GRIP-1 and CBP, a recruitment step that occurs before Ser81 phosphorylation and association with promoters of target genes.
UNLABELLED: Complete androgen insensitivity syndrome (CAIS) is a relatively rare X-linked disorder caused by androgen receptor gene (AR) mutations that result in complete impairment of genital virilisation. In these individuals, no müllerian derivatives are usually found; however, several sporadic cases of CAIS with müllerian remnants have been reported. In this paper, we report two novel point mutations of the AR gene resulting in two cases of CAIS with incomplete müllerian regression. Molecular studies of cases 1 and 2 showed novel missense mutations of the AR gene, with a methionine to threonine substitution at codon 749 (base 2608 T-->C) in exon 5 and a methionine to lysine substitution at codon 787 (base 2722 T-->A) in exon 6. Both patients received bilateral gonadectomy and inguinal hernia repair. The excised gonads proved to be testes with incomplete regression of the müllerian structures. CONCLUSION: Müllerian structures can be present in androgen insensitivity syndrome and the presence of a uterus therefore does not exclude this disorder. Further study of these patients may promote a better understanding of the pathogenesis.
As locally converted estrogen from testicular testosterone contributes to apparent androgen activity, the physiological significance of androgen receptor (AR) function in the beneficial effects of androgens on skeletal tissues has remained unclear. We show here that inactivation of AR in mice using a Cre-loxP system-mediated gene-targeting technique caused bone loss in males but not in females. Histomorphometric analyses of 8-week-old male AR knockout (ARKO) mice showed high bone turnover with increased bone resorption that resulted in reduced trabecular and cortical bone mass without affecting bone shape. Bone loss in orchidectomized male ARKO mice was only partially prevented by treatment with aromatizable testosterone. Analysis of primary osteoblasts and osteoclasts from ARKO mice revealed that AR function was required for the suppressive effects of androgens on osteoclastogenesis supporting activity of osteoblasts but not on osteoclasts. Furthermore, expression of the receptor activator of NF-kappaB ligand (RANKL) gene, which encodes a major osteoclastogenesis inducer, was found to be up-regulated in osteoblasts from AR-deficient mice. Our results indicate that AR function is indispensable for male-type bone formation and remodeling.