The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome
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 diagn...
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Published in | International journal of molecular sciences Vol. 21; no. 21; p. 8403 |
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Main Authors | , , , , , , , , , , , |
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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
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. |
---|---|
AbstractList | 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. 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. 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. |
Author | Livshits, Ludmila Kusz-Zamelczyk, Kamila Sajek, Malgorzata Sarkisian, Tamara Jaruzelska, Jadwiga Hayrapetyan, Hasmik Sajek, Marcin P Markosyan, Renata Stevenson, Brian J Nef, Serge Ilaslan, Erkut Sproll, Patrick |
AuthorAffiliation | 9 Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, CH-1211 Genève 4, Switzerland 1 Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland; erkut.ilaslan@igcz.poznan.pl (E.I.); marcin.sajek@igcz.poznan.pl (M.P.S.); jadwiga.jaruzelska@igcz.poznan.pl (J.J.) 4 SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; brian.stevenson@unil.ch 2 Endocrinology Department, “Muratsan” University Hospital, Endocrinology Clinic, Yerevan State Medical University, 0025 Yerevan, Armenia; renatamarkosyan@mail.ru 8 Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03143 Kyiv, Ukraine; livshits@edu.imbg.org.ua 6 Department of Medical Genetics, Yerevan State Medical University, 0025 Yerevan, Armenia; hasmik.hayrapetyan@cmg.am (H.H.); tamarasarkisyan@gmail.com (T.S.) 3 Division of Endocrinology, University of Fribourg, 1700 Fribourg, Switzerland; patrick.sproll@unifr.ch 5 Department of Human Molecular G |
AuthorAffiliation_xml | – name: 5 Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, 61-614 Poznan, Poland; grete@amu.edu.pl – name: 6 Department of Medical Genetics, Yerevan State Medical University, 0025 Yerevan, Armenia; hasmik.hayrapetyan@cmg.am (H.H.); tamarasarkisyan@gmail.com (T.S.) – name: 1 Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland; erkut.ilaslan@igcz.poznan.pl (E.I.); marcin.sajek@igcz.poznan.pl (M.P.S.); jadwiga.jaruzelska@igcz.poznan.pl (J.J.) – name: 3 Division of Endocrinology, University of Fribourg, 1700 Fribourg, Switzerland; patrick.sproll@unifr.ch – name: 2 Endocrinology Department, “Muratsan” University Hospital, Endocrinology Clinic, Yerevan State Medical University, 0025 Yerevan, Armenia; renatamarkosyan@mail.ru – name: 9 Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, CH-1211 Genève 4, Switzerland – name: 4 SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; brian.stevenson@unil.ch – name: 7 Center of Medical Genetics and Primary Health Care, 375010 Yerevan, Armenia – name: 8 Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03143 Kyiv, Ukraine; livshits@edu.imbg.org.ua |
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Keywords | partial androgen insensitivity syndrome (PAIS) disorder of sexual development (DSD) androgen receptor signaling FKBP4 androgen insensitivity syndrome (AIS) |
Language | English |
License | https://creativecommons.org/licenses/by/4.0 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
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Notes | These authors contributed equally to this work. |
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Snippet | Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations.... |
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SubjectTerms | 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 |
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Title | The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome |
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