Objective: Androgen insensitivity syndrome (AIS) due to androgen receptor (AR) mutations create a spectrum of clinical presentations based on residual AR function with the mildest impairment creating mild AIS (MAIS) whose undefined molecular mechanism and subtle clinical features leave it little understood and underdiagnosed.
Design: in silico modelling and in vitro androgen bioassay of the mutated AR to identify its structural and physiological mechanism. Describing clinical features and responses to high dose testosterone treatment of three cases of MAIS cases across a six-generation family pedigree.
Methods: Structural and dynamic in silico molecular modelling and in vitro yeast-based androgen bioassays of the mutant AR. Three cases of MAIS with consistent (gynecomastia, micropenis) and variable (infertility) clinical features across generations and effects of high dose testosterone treatment.
Results: The missense AR exon 8 mutation (nucleotide aga > gga, p.R872G arginine to glycine), known to cause increases ligand dissociation rate from mutant AR in binding assays, modelling shows the mutation weakens the closure energy of the "lid" of the ligand binding pocket allowing for easier ligand dissociation from binding site but with unimpaired in vitro androgen bioactivity. High dose testosterone treatment for 3 years in one young man caused increased virilisation and height growth but was ineffective for micropenis. Genetic counselling allowed effective prediction of MAIS risks in progeny for a carrier and non-carrier sisters.
Conclusions: The differential diagnosis and clinical management of MAIS is reviewed. The novel molecular mechanism of an AR ligand binding domain mutation in MAIS may be present in other case of MAIS.