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

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

doi:10.3390/ijms21218403

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Journal article

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

Ilaslan, Erkut Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
Markosyan, Renata Endocrinology Department, “Muratsan” University Hospital, Endocrinology Clinic, Yerevan State Medical University, 0025 Yerevan, Armenia
Sproll, Patrick Division of Endocrinology, University of Fribourg, 1700 Fribourg, Switzerland
Stevenson, Brian J. SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Sajek, Malgorzata Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, 61-614 Poznan, Poland
Sajek, Marcin P. Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
Hayrapetyan, Hasmik Department of Medical Genetics, Yerevan State Medical University, 0025 Yerevan, Armenia - Center of Medical Genetics and Primary Health Care, 375010 Yerevan, Armenia
Sarkisian, Tamara Department of Medical Genetics, Yerevan State Medical University, 0025 Yerevan, Armenia - Center of Medical Genetics and Primary Health Care, 375010 Yerevan, Armenia
Livshits, Ludmila Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03143 Kyiv, Ukraine
Nef, Serge Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, CH-1211 Genève 4, Switzerland
Jaruzelska, Jadwiga Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
Kusz-Zamelczyk, Kamila Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland

09.11.2020

Published in:

International Journal of Molecular Sciences. - 2020, vol. 21, no. 21, p. 8403

English 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.

Faculty

Faculté des sciences et de médecine

Department

Médecine 3ème année

Language