PubMed · 12652740
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Toshihiko Yanase, Masahiro Adachi, Ryoichi Takayanagi, Hajime Nawata. 2003-02-10. [Cofactor diseases].. https://pubmed.ncbi.nlm.nih.gov/12652740/
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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.
BACKGROUND: Androgen insensitivity syndrome (AIS) comprises a range of phenotypes from male infertility to complete feminization. Most individuals with AIS carry germline mutations of the androgen receptor (AR) that interfere with or ablate its function. As genital fibroblasts retain expression of the AR in vitro, we used genital skin fibroblasts from normal males and 46,XY females with complete AIS due to known AR mutations to gain insights into the role of the AR in human genital differentiation. RESULTS: Using DNA microarrays representing 32,968 different genes, we identified 404 transcripts with significant differences in transcription levels between genital skin fibroblasts cultured from normal and AIS-affected individuals. Gene-cluster analyses uncovered coordinated expression of genes involved in key processes of morphogenesis. On the basis of animal studies and human genetic syndromes, several of these genes are known to have specific roles in genital differentiation. Remarkably, genital fibroblasts from both normal and AIS-affected individuals showed no transcriptional response to dihydrotestosterone treatment despite expression of the AR. CONCLUSIONS: The results suggest that in addition to differences in the anatomic origin of the cells, androgen signaling during prenatal development contributes to setting long-lasting, androgen-independent transcriptional programs in genital fibroblasts. Our findings have broad implications in understanding the establishment and the stability of sexual dimorphism in human genital development.