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

• Published in: International journal of molecular sciences Vol. 21; no. 21; p. 8403
• Main Authors: Ilaslan, Erkut, Markosyan, Renata, Sproll, Patrick, Stevenson, Brian J, Sajek, Malgorzata, Sajek, Marcin P, Hayrapetyan, Hasmik, Sarkisian, Tamara, Livshits, Ludmila, Nef, Serge, Jaruzelska, Jadwiga, Kusz-Zamelczyk, Kamila
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 09.11.2020; MDPI AG
• Subjects: Amino Acid Sequence; Amino Acid Substitution - genetics; androgen insensitivity syndrome (AIS); androgen receptor signaling; Androgen-Insensitivity Syndrome - genetics; Child; Communication; disorder of sexual development (DSD); Exome - genetics; FKBP4; Humans; Male; Mutation - genetics; partial androgen insensitivity syndrome (PAIS); Receptors, Androgen - genetics; Sexual Development - genetics; Signal Transduction - genetics; Tacrolimus Binding Proteins - genetics; partial androgen insensitivity syndrome (PAIS); disorder of sexual development (DSD); androgen receptor signaling; FKBP4; androgen insensitivity syndrome (AIS)
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21218403

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for mutations is a routine approach in AIS diagnosis. However, some AIS patients lack mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking mutations. The whole exome sequencing of the patient and his family members identified a heterozygous 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 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 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking gene mutations.