Objective: To understand the pathogenesis of the androgen insensitivity syndrome.
Design: Familial case study.
Setting: Medical and Evolutionary Genetics Laboratory, Centre for Cellular and Molecular Biology, Hyderabad, India.
Patient(s): Two affected sisters and other unaffected family members.
Intervention(s): The hormone levels were measured by RIA. Histology was done by standard protocols. DNA isolation and direct DNA sequencing was undertaken for mutation identification. Site-directed mutagenesis was used for incorporation of mutation in the androgen receptor clone. Functional assays were done using COS-1 cell cultures.
Main outcome measure(s): Phenotype, hormone levels, DNA mutations, ligand binding, transactivation function of androgen-androgen receptor complex.
Result(s): The patients exhibited a female phenotype despite the 46,XY chromosome complement. Both of the affected individuals had higher levels of T and LH. C1760A (coding DNA sequence reference) substitution (Ala 586 Asp) in the AR gene was observed in all of the affected individuals. The mutation did not result in a loss of ligand binding but instead in almost complete loss of transactivation function.
Conclusion(s): The Ala 586 Asp mutation resulted in a complete loss of transactivation function of the androgen-androgen receptor complex but did not affect ligand binding. In vitro assays confirmed the pathogenic nature of this mutation.