Functional Analysis of Six Androgen Receptor Mutations Identified in Patients with Partial Androgen Insensitivity Syndrome

• Published in: Human molecular genetics Vol. 5; no. 2; pp. 265 - 273
• Main Authors: Bevan, Charlotte L., Brown, Betty B., Davies, Helen R., Evans, Bronwen A. J., Hughes, Ieuan A., Patterson, Mark N.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.1996
• Subjects: Amino Acid Sequence; Androgens - pharmacology; Biological and medical sciences; Cell Line; Disorders of Sex Development - etiology; Disorders of Sex Development - genetics; Endocrine System Diseases - etiology; Endocrine System Diseases - genetics; Gynecology. Andrology. Obstetrics; HeLa Cells; Humans; Male and female genital diseases. Gonadal dysgenesis. Hermaphroditism. Sex hormones resistance; Medical sciences; Molecular Sequence Data; Mutation; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Sequence Homology, Amino Acid; Transcriptional Activation; Human; Nuclear receptor; Androgen; Molecular interaction; Binding site; Male pseudohermaphroditism; Genetic disease; Target tissue resistance; Phenotype; Gene; Partial; Mutation; Sex steroid hormone; Male genital diseases; Hormonal receptor
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/5.2.265

Partial androgen insensitivity syndrome (PAIS) is caused by defects in the androgen receptor gene and presents with a wide range of undervirilization pheno-types. We studied the consequences of six androgen receptor ligand-binding domain mutations on receptor function in transfected cells. The mutations, Met742Ile, Met780Ile, Gln798Glu, Arg840Cys, Arg855His and Ile869Met, were identified in PAIS patients with pheno-types representing the full spectrum seen in this condition. In all cases the androgen receptor was found to be defective, suggesting that the mutation is the cause of the clinical phenotype. The Gln798Glu mutation is exceptional in that it did not cause an androgen-binding defect in our system, although the mutant receptor was defective assays. This mutation may affect an aspect of binding not tested, or may be part of a functional subdomain of the ligand-binding domain involved in transactivation. Overall we found milder mutations to be associated with milder clinical phenotypes. There is also clear evidence that pheno-type is not solely dependent on androgen receptor function. Some of the mutant receptors were able to respond to high doses of androgen in vitro, suggesting that patients carrying these mutations may be the best candidates for androgen therapy. One such mutation is Ile869Met. A patient carrying this mutation has virilized spontaneously at puberty, so in vivo evidence agrees with the experimental result. Thus a more complete understanding of the functional consequences of androgen receptor mutations may provide a more rational basis for gender assignment in PAIS.