The FKBP4 gene, encoding a regulator of the androgen receptor signaling pathway, is a novel candidate gene for androgen insensitivity syndrome

Ilaslan E,Sajek Mp,Markosyan R,Sproll P,Livshits L,Sarkisian T,Nef S,Stevenson Bj,Sajek M,Jaruzelska J,Kusz-Zamelczyk K,Hayrapetyan H

doi:10.1530/ey.18.6.3

Abstract

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.

Highlights

Androgens govern the development of reproductive and non-reproductive pathways of the male body during the successive life periods, resulting in human sexual dimorphism
The function of that gene is linked to an androgen receptor (AR) signaling pathway, i.e., the FKBP4 protein interacts with AR [5] and its chaperone Hsp90 [6], leading to enhanced androgen binding and the upregulation of AR-mediated transcription [7,8,9,10]
A search for a FKBP4 gene mutation in a group of patients with hypospadias was described but no variant associated with that condition was found [25]

Summary

Introduction

Androgens govern the development of reproductive and non-reproductive pathways of the male body during the successive life periods, resulting in human sexual dimorphism. Androgens act via the androgen receptor (AR) signaling pathway They bind to the AR in the AR-Hsp90-p23 heterocomplex located within the cytoplasm of androgen-sensitive cells, cause AR activation and translocation into the nucleus, whereby AR functions as a transcription factor of specific genes; for a review, see [3,4]. The expression of these genes, in turn, stimulates cell growth, proliferation, cell cycle progression as well as secretion of specific proteins by AR-expressing cells, resulting in the development of a male phenotype; for review see [3]. Thanks to the FKBP4–Hsp interaction, the AR receptor gains a high affinity for hormone binding and the AR-mediated transcription becomes upregulated [7,8,9,10]

Methods

Results

Conclusion