Human Molecular Genetics, Vol 5, 265-273, Copyright © 1996 by Oxford University Press
CL Bevan, BB Brown, HR Davies, BA Evans, IA Hughes and MN Patterson
Partial androgen insensitivity syndrome (PAIS) is caused by defects in the
androgen receptor gene and presents with a wide range of undervirilization
phenotypes. 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 phenotypes 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 in transactivation 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 phenotype 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.
ARTICLES
Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome
University Department of Paediatrics, University of Cambridge, UK.
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