The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome

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.

Pubertal and Gonadal Outcomes in 46,XY Individuals with Partial Androgen Insensitivity Syndrome Raised as Girls

“…Although our cohort was small, the fact that we included only individuals with molecularly proven AR variants represents a strength of our study. Earlier studies of cohorts with the presumptive diagnosis of PAIS but without molecular confirmation of AR variants, have led to assumptions on a mixed bag of diagnoses, ranging from mild forms of gonadal dysgenesis and deficiencies in steroidogenesis [Boehmer et al, 2001], to phenocopies of PAIS involving mutations in other molecular members of the AR signaling pathway [Hornig et al, 2016;Ilaslan et al, 2020]. As a result of low-stringency diagnoses, much of the prognostic information for PAIS to date may have been unreliable, even for key outcomes such as neoplasia risk.…”

Pubertal And Gonadal Outcomes In 46,XY Individuals With Partial Androgen Insensitivity Syndrome Raised As Girls

“…Although our cohort was small, the fact that we included only individuals with molecularly proven AR variants represents a strength of our study. Earlier studies of cohorts with the presumptive diagnosis of PAIS but without molecular con rmation of AR variants, have led to assumptions based on a mixed bag of diagnoses, ranging from mild forms of gonadal dysgenesis and de ciencies in steroidogenesis [3], to phenocopies of PAIS involving mutations in other molecular members of the AR signaling pathway [16,17]. As a result of low stringency diagnoses much of the prognostic information for PAIS to date may have been unreliable, even for key outcomes such as neoplasia risk.…”

Mutations in Hsp90 Cochaperones Result in a Wide Variety of Human Disorders

“…Other genetic variations in FKBP6 have been linked to the neurodevelopmental disorder Williams-Beuren syndrome ( Metcalfe et al, 2005 ), congenital heart malformations ( Tomita-Mitchell et al, 2012 ) and male infertility ( Zhang et al, 2007 ; Greither et al, 2020 ). Loss of function alleles of FKBPL have also been associated with male infertility ( Sengun et al, 2021 ), and a mutation in FKBP4 has been associated with androgen insensitivity ( Ilaslan et al, 2020 ).…”

“…For example, the GR is one of the most widely studied Hsp90 clients, and changes in activity of GR and/or other clients due to altered abundance of associated cochaperones has been linked to mood disorders, autism, anxiety, psychotic illness, depression, and altered pain susceptibility ( Sinclair et al, 2013 ; Patel et al, 2016 ; Baker et al, 2018 ; Lee et al, 2019 ; Lou et al, 2021 ; Mokha et al, 2021 ; Salhi et al, 2021 ; Szczepankiewicz et al, 2021 ). Similarly, androgen receptor activity is highly dependent on cochaperones encoded by FKBP4, FKBPL, and SGTA ( Paul et al, 2014 ; Ilaslan et al, 2020 ; Sengun et al, 2021 ).…”