HGM2002 Poster Abstracts: 8. Disease Mechanisms
POSTER NO: 477
Arg840Cys Substitution in Androgen Receptor in a Large Chinese Family and the Pleiotropic Effects of the Mutant
1Zhen Zhang, 2Zhimin Zhao, 1Jianhua Chu, 1Rongmei Zhang, 1Jiu-Cun Wang, 1Minghua Wang, 1Qingyan Fei, 1Wei Zou, 1Yefei Han, 1Qingyuan Qi, 1Hongtao Zhang, 1Shisheng Tao, 1Xiaoming Liu, 1Zewei Luo
Androgen insensitivity syndrome (AIS) is a genetic disorder of male sexual development caused by an absent or dysfunctional androgen receptor (AR). Fertile cases with mild AIS and slightly impaired AR activity had been reported in literature, and their external genitalia were documented to be usually normal or subnormal. We reported here an Arg840Cys substitution in the AR gene in a large Chinese pedigree affected with highly divergent clinical phenotypes of AIS.
The pedigree consists of over 100 individuals including 14 affected males. The proband was born with penile hypospadias, and bilateral gynecomastia occurred at his age of 17 yr. Then his hypospadias and bilateral gynecomastia were surgically corrected and he fathered a healthy boy at age of 27yr. Other patients, including his cousins, maternal uncles, maternal grandfather and one brother of this grandfather, expressed divergent phenotypes such as impaltable or small laryngeal protuberance, scanty or sparse pubic hair, different hypospadias type, normal or bifid scrotum and etc. Despite of the divergence of phenotypes, these patients carried an identical mutation, a single base substitution of C to T at site 3851 in exon 7 of AR gene, which causes an Arg840Cys substitution and disruption of a Pvu^T site. The mutant gene may result in infertility for some affected males with or without hypospadias. However, it was also observed that the mutation did not affect the fertility of the other patients. The gonadotropin levels and semen level for one of these fertile patients were found within the normal range. This observation stimulates our attempt to elucidate the pleiotropic effect of the AR mutant.
Three strains of fibroblast were cultured from patient genital skin biopsy and the androgen binding activity in these fibroblasts were measured. Then, trans-activation function of the AR gene among these cell lines were investigated. It has been a historical problem that the introduction of plasmids carrying reporter genes into primary genital skin fibroblast (GSF) is not efficient. In this report, we modified a transfection kit to efficiently deliver reporter genes into recipient GSF strains. It enabled us to directly assess the endogenous mutant AR function. The success of the experiment may make the kit a valuable tool in analysis of the function of mutant ARs. At the same time the differentiation in transcriptional and translational levels of ARs of these patients were also clarified by means of Northern and Western blots.
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