Reduced androgen receptor gene expression with first exon CAG repeat expansion.
The molecular basis for partial androgen insensitivity associated with adult onset spinal/bulbar muscular atrophy was investigated by transient transfection of human androgen receptor (AR) expression vectors containing increasing CAG repeat lengths in the first exon. An inverse relationship was observed between CAG repeat length and AR mRNA and protein levels. Trinucleotide repeat lengths of 43 and 65 associated with spinal/bulbar muscular atrophy decreased AR mRNA and protein levels but did not alter equilibrium binding affinity for [3H]R1881 or inherent transcriptional activity of AR, expressed as androgen-dependent fold induction of a mouse mammary tumor virus promoter-luciferase reporter vector. The findings indicate that glutamine expansion up to 66 residues in the NH2-terminal domain of AR does not alter AR functional activity. Rather, CAG repeat expansion in the region of the first exon reduces AR mRNA and protein expression. The study reveals a previously unrecognized effect of CAG repeat length on AR mRNA expression and a novel molecular mechanism for androgen resistance.
Choong
C S
CS
Laboratories for Reproductive Biology, University of North Carolina, Chapel Hill 27599-7500, USA.
Kemppainen
J A
JA
Zhou
Z X
ZX
Wilson
E M
EM
D000728:Androgens / Q000378:metabolism; D000818:Animals; D019556:COS Cells / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D009134:Muscular Atrophy, Spinal / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011944:Receptors, Androgen / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D014162:Transfection; D018911:Trinucleotide Repeats
D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011994:Recombinant Proteins