Preserved Fertility in a Patient with Gynecomastia Associated with the p.Pro695Ser Mutation in the Androgen Receptor

Author(s)

Petroli, Reginaldo J. ^{[1, 2]} ; Hiort, Olaf ^[1] ; Struve, Dagmar ^[1] ; Maciel-Guerra, Andrea T. ^[3] ; Guerra-Junior, Gil ^[4] ; de Mello, Maricilda Palandi ^[2] ; Werner, Ralf ^[1]

Affiliation

^[1] Med Univ Lubeck, Dept Paediat & Adolescent Med, Div Expt Paediat Endocrinol & Diabet, D-23538 Lubeck - Germany

^[2] Univ Estadual Campinas, Fac Ciencias Med, CBMEG, Campinas, SP - Brazil

^[3] Univ Estadual Campinas, Fac Ciencias Med, Dept Med Genet, Campinas, SP - Brazil

^[4] Univ Estadual Campinas, Fac Ciencias Med, Dept Pediat, Campinas, SP - Brazil

• Document type: Journal article
• Source: SEXUAL DEVELOPMENT; v. 8, n. 6, p. 350-355, 2014.
• Web of Science Citations: 3

Abstract

The androgen insensitivity syndrome (AIS) is described as a dysfunction of the androgen receptor (AR) in 46, XY individuals, which can be associated with mutations in the AR gene or can be due to unknown mechanisms. Different mutations in AIS generally cause variable phenotypes that range from a complete hormone resistance to a mild form usually associated with male infertility. The purpose of this study was to search for mutations in the AR gene in a fertile man with gynecomastia and to evaluate the influence of the mutation on the AR transactivation ability. Sequencing of the AR gene revealed the p.Pro695Ser mutation. It is located within the AR ligand-binding domain. Bioinformatics analysis indicated a deleterious role, which was verified after testing transactivation activity and N-/C-terminal (N/C) interaction by in vitro expression of a reporter gene and 2-hybrid assays. p.Pro695Ser showed low levels of both transactivation activity and N/C interaction at low dihydrotestosterone (DHT) conditions. As the ligand concentration increased, both transactivation activity and N/C interaction also increased and reached normal levels. Therefore, this study provides functional insights for the p.Pro695Ser mutation described here for the first time in a patient with mild AIS. The expression profile of p.Pro695Ser not only correlates to the patient's phenotype, but also suggests that a high-dose DHT therapy may overcome the functional deficit of the mutant AR. (C) 2014 S. Karger AG, Basel (AU)

• FAPESP's process: 08/01964-5 - Molecular analysis of the androgen receptor gene (AR) in patients 46,XY presenting genital ambiguity and normal testosterone production
• Grantee: Reginaldo José Petroli
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 09/08320-9 - Serching for mutations on ar and SRD5A2 genes in 46,XY newborn and pre-pubarche patients with genital ambiguity
• Grantee: Maricilda Palandi de Mello
• Support Opportunities: Regular Research Grants