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PMID:2341409

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Citation

Yarbrough, WG, Quarmby, VE, Simental, JA, Joseph, DR, Sar, M, Lubahn, DB, Olsen, KL, French, FS and Wilson, EM (1990) A single base mutation in the androgen receptor gene causes androgen insensitivity in the testicular feminized rat. J. Biol. Chem. 265:8893-900

Abstract

The complete form of androgen insensitivity is an inherited X-linked syndrome in which genetic males fail to undergo masculinization in utero due to defective functioning of the androgen receptor (AR). The molecular basis of androgen insensitivity was investigated in the testicular feminized (Tfm) rat with this syndrome. AR mRNA size and amount, as well as nuclear AR protein revealed by immunocytochemistry, suggested normal expression of the AR gene in the Tfm rat. Sequence analysis of the AR coding region from Tfm and wild-type littermate male rats revealed a single transition mutation, guanine to adenine, within exon E, changing arginine 734 to glutamine within the steroid-binding domain of the AR. This arginine is highly conserved among the family of nuclear receptors and may be part of a phosphorylation recognition site. A recreated mutant AR (Arg734----Gln) expressed in COS cells had only 10-15% of the androgen-binding capacity of wild-type AR; the reduced androgen-binding capacity was similar to that of AR in tissue extracts of the Tfm rat. Stimulation of transcriptional activity by the recreated mutant AR was reduced relative to wild-type AR in cotransfection assays in CV1 cells using as reporter plasmid the mouse mammary tumor virus promoter linked to the chloramphenicol acetyltransferase gene. Thus, arginine 734 appears essential for normal AR function both in androgen binding and transcriptional activation. Absence of these functions results in androgen insensitivity and lack of male sexual development.

Links

PubMed

Keywords

Amino Acid Sequence; Androgens/metabolism; Animals; Base Sequence; Cell Line; DNA/genetics; Feminization/genetics; Feminization/metabolism; Gene Amplification; Humans; Male; Molecular Sequence Data; Mutation; RNA, Messenger/genetics; RNA, Messenger/isolation & purification; Rats; Rats, Mutant Strains; Receptors, Androgen/genetics; Receptors, Androgen/metabolism; Restriction Mapping; Sequence Homology, Nucleic Acid; Transfection; X Chromosome

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:ANDR

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:ANDR

involved_in

GO:0030521: androgen receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:ANDR

involved_in

GO:0046661: male sex differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:ANDR

involved_in

GO:0071383: cellular response to steroid hormone stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:ANDR

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:ANDR

enables

GO:0005497: androgen binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:ANDR

enables

GO:0004879: nuclear receptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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