A new mutation of the androgen receptor, P817A, causing partial androgen insensitivity syndrome: in vitro and structural analysis.
Androgen insensitivity syndrome (AIS) is an X-linked disease caused by mutations in the androgen receptor (AR) resulting in various degrees of defective masculinization in 46,XY individuals. In the present study, we describe a novel mutation in exon 7 of the AR gene in an Egyptian patient with partial AIS (PAIS). Sequencing analysis of the AR gene revealed a novel missense mutation, P817A, within the ligand-binding domain (LBD). This is the first report of a mutation within the short amino acid motif (codons 815-817) of the beta-strand lying between helices H8 and H9 of the AR LBD. The functional defects of the mutated protein were characterized by in vitro study and included significantly decreased ligand-binding affinity and impaired transactivation potential. Limited proteolysis assays performed with the wild-type and mutant AR receptors incubated with the synthetic agonist R1881 revealed that the P817A mutation resulted in a reduced stabilization of the AR active conformation. Structural analyses showed that this mutation is likely to perturb the beta-sheet interaction between residues 815-817 and 911-913. This structural alteration destabilizes the position of the C-terminal extension, which contains residues critical for androgen function.
Lumbroso
S
S
Institut National de la Santé et de la Recherche Médicale, INSERM U540, Endocrinologie Moléculaire et Cellulaire des Cancers, Montpellier, France.
Wagschal
A
A
Bourguet
W
W
Georget
V
V
Mazen
I
I
Servant
N
N
Audran
F
F
Sultan
C
C
Auzou
G
G
D013734:Androgen-Insensitivity Syndrome / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D008297:Male; D008958:Models, Molecular; D025202:Molecular Diagnostic Techniques; D015394:Molecular Structure; D020125:Mutation, Missense; D011487:Protein Conformation; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D011944:Receptors, Androgen