Comparison of the molecular consequences of different mutations at residue 754 and 690 of the androgen receptor (AR) and androgen insensitivity syndrome (AIS) phenotype.

OBJECTIVE: Androgen insensitivity syndrome (AIS) is associated with mutations throughout the androgen receptor (AR) gene. Different mutations at the same codon have been identified in individuals with various phenotypes suggesting the nature of the codon substituted may influence the degree of AIS. We investigated if phenotype could be predicted by comparing the functionality of AR mutations with those at the same codon of known phenotype.

PATIENTS: We identified patients from the Cambridge Disorders of Sex Development Database with the AR substitutions: Phe754Ser with microphallus without hypospadias and Asp690Val with complete AIS. Mutations Phe754Leu, Phe754Val and Asp690deletion (Asp690del) have previously been reported to be associated with different degrees of AIS.

DESIGN: We characterized the functional properties of Phe754Ser, Phe754Leu, Phe754Val, Asp690Val and Asp690del receptor mutants in vitro and used the crystal structure of the AR ligand binding domain to model the mutations.

RESULTS: The receptor mutants Phe754Ser, Phe754Leu and Phe754Val bound androgen with decreasing affinity, while Asp690Val showed reduced affinity compared to Asp690del. A similar pattern of reduced activation was seen on androgen responsive elements. We suggest how the mutations could affect AR structure, resulting in the observed phenotypes.

CONCLUSIONS: The relative functional properties of Phe754 and Asp690 mutant AR receptors correlate broadly with their specific phenotypes. Therefore, comparing the molecular consequences of novel mutations with others at the same codon may be a useful aid to AIS patient management, particularly for sex of rearing decisions when prediction of functionality is important.