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 inInternational 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
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LanguageEnglish
Published Switzerland MDPI 09.11.2020
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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
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Issue 21
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
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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
URI https://www.ncbi.nlm.nih.gov/pubmed/33182400
https://pubmed.ncbi.nlm.nih.gov/PMC7664851
https://doaj.org/article/95545f9b3253405f88d6a1584e7aa4fb
Volume 21
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