Dissecting phenotypic variation among AIS patients.
We have created genital skin fibroblast cell lines directly from three patients in a Chinese family affected by androgen insensitivity syndrome (AIS). All patients in the family share an identical AR Arg840Cys mutant but show different disease phenotypes. By using the cell lines, we find that the mutation has not influenced a normal androgen-binding capacity at 37 degrees C but has reduced the affinity for androgens and may cause thermolability of the androgen-receptor complex. The impaired nuclear trafficking of the androgen receptor in the cell lines is highly correlated with the severity of donors' disease phenotype. The transactivity of the mutant is substantially weakened and the extent of the reduced transactivity reflects severity of the donors' disease symptom. Our data reveal that although etiology of AIS is monogenic and the mutant may alter the major biological functions of its wild allele, the function of the mutant AR can also be influenced by the different genetic backgrounds and thus explains the divergent disease phenotypes.
Wang
Minghua
M
Laboratory of Population and Quantitative Genetics, China's State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Morgan-Tan International Center for Life Sciences, Fudan University, Shanghai, PR China.
Wang
Jiucun
J
Zhang
Zhen
Z
Zhao
Zhimin
Z
Zhang
Rongmei
R
Hu
Xiaohua
X
Tan
Tao
T
Luo
Shijing
S
Luo
Zewei
Z
D000328:Adult; D013734:Androgen-Insensitivity Syndrome / Q000175:diagnosis* / Q000235:genetics*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000737:chemistry; D015152:Blotting, Northern; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D002681:China; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D004247:DNA / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D017930:Genes, Reporter; D014644:Genetic Variation; D006801:Humans; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009154:Mutation; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism; D013696:Temperature; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D000728:Androgens; D011944:Receptors, Androgen; D004247:DNA; D001120:Arginine; D008156:Luciferases; D003545:Cysteine