Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies.

Marie-France Portnoi, Marie-Charlotte Dumargne, Sandra Rojo, Selma F. Witchel, Andrew J. Duncan, Caroline Eozenou, Joelle Bignon-Topalovic, Sventlana A. Yatsenko, Aleksandar Rajkovic, Miguel Reyes-Mugica, Kristian Almstrup, Lelia Fusee, Yogesh Srivastava, Sandra Chantot-Bastaraud, Capucine Hyon, Christine Louis-Sylvestre, Pierre Validire, Caroline de Malleray Pichard, Celia Ravel, Sophie Christin-MaitreRaja Brauner, Raffaella Rossetti, Luca Persani, Eduardo H. Charreau, Liliana Dain, Violeta A. Chiauzzi, Inas Mazen, Hassan Rouba, Caroline Schluth-Bolard, Stuart MacGowan, W. H. Irwin McLean, Etienne Patin, Ewa Rajpert-De Meyts, Ralf Jauch, John C. Achermann, Jean-Pierre Siffroi, Ken McElreavey, Anu Bashamboo

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Abstract

SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but the role of SOX8 in humans is unknown. Here, we show that SOX8 is expressed in the somatic cells of the early developing gonad in the human and influences human sex-determination. We identified two individuals with 46,XY disorders/differences in sex development (DSD) and chromosomal rearrangements encompassing the SOX8 locus and a third individual with 46,XY DSD and a missense mutation in the HMG-box of SOX8. In-vitro functional assays indicate that this mutation alters the biological activity of the protein. As an emerging body of evidence suggests that DSDs and infertility can have common etiologies, we also analyzed SOX8 in a cohort of infertile men (n = 274) and two independent cohorts of women with primary ovarian insufficiency (POI; n = 153 and n = 104). SOX8 mutations were found at increased frequency in oligozoospermic men (3.5%; p<0.05) and POI (5.06%; p=4.5x10-5) as compared to fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared to the wild-type protein. These data demonstrate that SOX8 plays an important role in human reproduction and SOX8 mutations contribute to a spectrum of phenotypes including 46,XY DSD, male infertility and 46,XX POI.

Original languageEnglish
Pages (from-to)1228-1240
Number of pages13
JournalHuman Molecular Genetics
Volume27
Issue number7
Early online date24 Jan 2018
DOIs
Publication statusPublished - 1 Apr 2018

Fingerprint

Sexual Development
Mutation
Genes
Primary Ovarian Insufficiency
Male Infertility
Gene Deletion
Gonads
Missense Mutation
Mutant Proteins
Infertility
Reproduction
Proteins
Transcription Factors
Phenotype
Population

Keywords

  • Journal article
  • Phenotype
  • Turner's syndrome
  • Mutation
  • Chromosome rearrangements
  • Fertility
  • Genes

Cite this

Portnoi, M-F., Dumargne, M-C., Rojo, S., Witchel, S. F., Duncan, A. J., Eozenou, C., ... Bashamboo, A. (2018). Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies. Human Molecular Genetics, 27(7), 1228-1240. https://doi.org/10.1093/hmg/ddy037
Portnoi, Marie-France ; Dumargne, Marie-Charlotte ; Rojo, Sandra ; Witchel, Selma F. ; Duncan, Andrew J. ; Eozenou, Caroline ; Bignon-Topalovic, Joelle ; Yatsenko, Sventlana A. ; Rajkovic, Aleksandar ; Reyes-Mugica, Miguel ; Almstrup, Kristian ; Fusee, Lelia ; Srivastava, Yogesh ; Chantot-Bastaraud, Sandra ; Hyon, Capucine ; Louis-Sylvestre, Christine ; Validire, Pierre ; de Malleray Pichard, Caroline ; Ravel, Celia ; Christin-Maitre, Sophie ; Brauner, Raja ; Rossetti, Raffaella ; Persani, Luca ; Charreau, Eduardo H. ; Dain, Liliana ; Chiauzzi, Violeta A. ; Mazen, Inas ; Rouba, Hassan ; Schluth-Bolard, Caroline ; MacGowan, Stuart ; McLean, W. H. Irwin ; Patin, Etienne ; Rajpert-De Meyts, Ewa ; Jauch, Ralf ; Achermann, John C. ; Siffroi, Jean-Pierre ; McElreavey, Ken ; Bashamboo, Anu. / Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 7. pp. 1228-1240.
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title = "Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies.",
abstract = "SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but the role of SOX8 in humans is unknown. Here, we show that SOX8 is expressed in the somatic cells of the early developing gonad in the human and influences human sex-determination. We identified two individuals with 46,XY disorders/differences in sex development (DSD) and chromosomal rearrangements encompassing the SOX8 locus and a third individual with 46,XY DSD and a missense mutation in the HMG-box of SOX8. In-vitro functional assays indicate that this mutation alters the biological activity of the protein. As an emerging body of evidence suggests that DSDs and infertility can have common etiologies, we also analyzed SOX8 in a cohort of infertile men (n = 274) and two independent cohorts of women with primary ovarian insufficiency (POI; n = 153 and n = 104). SOX8 mutations were found at increased frequency in oligozoospermic men (3.5{\%}; p<0.05) and POI (5.06{\%}; p=4.5x10-5) as compared to fertile/normospermic control populations (0.74{\%}). The mutant proteins identified altered SOX8 biological activity as compared to the wild-type protein. These data demonstrate that SOX8 plays an important role in human reproduction and SOX8 mutations contribute to a spectrum of phenotypes including 46,XY DSD, male infertility and 46,XX POI.",
keywords = "Journal article, Phenotype , Turner's syndrome , Mutation , Chromosome rearrangements , Fertility , Genes",
author = "Marie-France Portnoi and Marie-Charlotte Dumargne and Sandra Rojo and Witchel, {Selma F.} and Duncan, {Andrew J.} and Caroline Eozenou and Joelle Bignon-Topalovic and Yatsenko, {Sventlana A.} and Aleksandar Rajkovic and Miguel Reyes-Mugica and Kristian Almstrup and Lelia Fusee and Yogesh Srivastava and Sandra Chantot-Bastaraud and Capucine Hyon and Christine Louis-Sylvestre and Pierre Validire and {de Malleray Pichard}, Caroline and Celia Ravel and Sophie Christin-Maitre and Raja Brauner and Raffaella Rossetti and Luca Persani and Charreau, {Eduardo H.} and Liliana Dain and Chiauzzi, {Violeta A.} and Inas Mazen and Hassan Rouba and Caroline Schluth-Bolard and Stuart MacGowan and McLean, {W. H. Irwin} and Etienne Patin and {Rajpert-De Meyts}, Ewa and Ralf Jauch and Achermann, {John C.} and Jean-Pierre Siffroi and Ken McElreavey and Anu Bashamboo",
note = "A.B is funded in part by the program Actions Concertees Interpasteuriennes (ACIP) and a research grant from the European Society of Pediatric Endocrinology. A. B and K. McE are funded by a research grant from the EuroDSD in the European Community’s Seventh Framework Programme FP7/2007-2013 under grant agreement n° 201444 as well as grant N°295097 as part of the EU call FP7-INCO-2011-6. The work is also funded by a FrancoEgyptian AIRD-STDF grant (A.B., K.M., I.M.). Y.S. thanks the Chinese Government Scholarship and University of the Chinese Academy of Science (UCAS) for financial and infrastructure support. R.J. is supported by a 2013 MOST China-EU Science and Technology Cooperation Program, Grant No. 2013DFE33080, by the National Natural Science Foundation of China (Grant No. 31471238) and a 100 talent award of the Chinese Academy of Sciences. K.A. is supported by the Innovation Fund Denmark (grant # 14-2013-4). The human embryonic and fetal material was provided by the Joint MRC/Wellcome Trust (grant #099175/Z/12/Z) Human Developmental Biology Resource (www.hdbr.org). J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science (098513/Z/12/Z) and received support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. R.R. is a fellow supported by the Italian Ministry of Health, Rome, Italy (grant # GR-2011-02351636). This work is supported by the COST Action DSDnet BM1303.",
year = "2018",
month = "4",
day = "1",
doi = "10.1093/hmg/ddy037",
language = "English",
volume = "27",
pages = "1228--1240",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "7",

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Portnoi, M-F, Dumargne, M-C, Rojo, S, Witchel, SF, Duncan, AJ, Eozenou, C, Bignon-Topalovic, J, Yatsenko, SA, Rajkovic, A, Reyes-Mugica, M, Almstrup, K, Fusee, L, Srivastava, Y, Chantot-Bastaraud, S, Hyon, C, Louis-Sylvestre, C, Validire, P, de Malleray Pichard, C, Ravel, C, Christin-Maitre, S, Brauner, R, Rossetti, R, Persani, L, Charreau, EH, Dain, L, Chiauzzi, VA, Mazen, I, Rouba, H, Schluth-Bolard, C, MacGowan, S, McLean, WHI, Patin, E, Rajpert-De Meyts, E, Jauch, R, Achermann, JC, Siffroi, J-P, McElreavey, K & Bashamboo, A 2018, 'Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies.', Human Molecular Genetics, vol. 27, no. 7, pp. 1228-1240. https://doi.org/10.1093/hmg/ddy037

Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies. / Portnoi, Marie-France; Dumargne, Marie-Charlotte; Rojo, Sandra; Witchel, Selma F.; Duncan, Andrew J.; Eozenou, Caroline; Bignon-Topalovic, Joelle; Yatsenko, Sventlana A.; Rajkovic, Aleksandar; Reyes-Mugica, Miguel; Almstrup, Kristian; Fusee, Lelia; Srivastava, Yogesh; Chantot-Bastaraud, Sandra; Hyon, Capucine; Louis-Sylvestre, Christine; Validire, Pierre; de Malleray Pichard, Caroline; Ravel, Celia; Christin-Maitre, Sophie; Brauner, Raja; Rossetti, Raffaella; Persani, Luca; Charreau, Eduardo H.; Dain, Liliana; Chiauzzi, Violeta A.; Mazen, Inas; Rouba, Hassan; Schluth-Bolard, Caroline; MacGowan, Stuart; McLean, W. H. Irwin; Patin, Etienne; Rajpert-De Meyts, Ewa; Jauch, Ralf; Achermann, John C.; Siffroi, Jean-Pierre; McElreavey, Ken; Bashamboo, Anu (Lead / Corresponding author).

In: Human Molecular Genetics, Vol. 27, No. 7, 01.04.2018, p. 1228-1240.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies.

AU - Portnoi, Marie-France

AU - Dumargne, Marie-Charlotte

AU - Rojo, Sandra

AU - Witchel, Selma F.

AU - Duncan, Andrew J.

AU - Eozenou, Caroline

AU - Bignon-Topalovic, Joelle

AU - Yatsenko, Sventlana A.

AU - Rajkovic, Aleksandar

AU - Reyes-Mugica, Miguel

AU - Almstrup, Kristian

AU - Fusee, Lelia

AU - Srivastava, Yogesh

AU - Chantot-Bastaraud, Sandra

AU - Hyon, Capucine

AU - Louis-Sylvestre, Christine

AU - Validire, Pierre

AU - de Malleray Pichard, Caroline

AU - Ravel, Celia

AU - Christin-Maitre, Sophie

AU - Brauner, Raja

AU - Rossetti, Raffaella

AU - Persani, Luca

AU - Charreau, Eduardo H.

AU - Dain, Liliana

AU - Chiauzzi, Violeta A.

AU - Mazen, Inas

AU - Rouba, Hassan

AU - Schluth-Bolard, Caroline

AU - MacGowan, Stuart

AU - McLean, W. H. Irwin

AU - Patin, Etienne

AU - Rajpert-De Meyts, Ewa

AU - Jauch, Ralf

AU - Achermann, John C.

AU - Siffroi, Jean-Pierre

AU - McElreavey, Ken

AU - Bashamboo, Anu

N1 - A.B is funded in part by the program Actions Concertees Interpasteuriennes (ACIP) and a research grant from the European Society of Pediatric Endocrinology. A. B and K. McE are funded by a research grant from the EuroDSD in the European Community’s Seventh Framework Programme FP7/2007-2013 under grant agreement n° 201444 as well as grant N°295097 as part of the EU call FP7-INCO-2011-6. The work is also funded by a FrancoEgyptian AIRD-STDF grant (A.B., K.M., I.M.). Y.S. thanks the Chinese Government Scholarship and University of the Chinese Academy of Science (UCAS) for financial and infrastructure support. R.J. is supported by a 2013 MOST China-EU Science and Technology Cooperation Program, Grant No. 2013DFE33080, by the National Natural Science Foundation of China (Grant No. 31471238) and a 100 talent award of the Chinese Academy of Sciences. K.A. is supported by the Innovation Fund Denmark (grant # 14-2013-4). The human embryonic and fetal material was provided by the Joint MRC/Wellcome Trust (grant #099175/Z/12/Z) Human Developmental Biology Resource (www.hdbr.org). J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science (098513/Z/12/Z) and received support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. R.R. is a fellow supported by the Italian Ministry of Health, Rome, Italy (grant # GR-2011-02351636). This work is supported by the COST Action DSDnet BM1303.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but the role of SOX8 in humans is unknown. Here, we show that SOX8 is expressed in the somatic cells of the early developing gonad in the human and influences human sex-determination. We identified two individuals with 46,XY disorders/differences in sex development (DSD) and chromosomal rearrangements encompassing the SOX8 locus and a third individual with 46,XY DSD and a missense mutation in the HMG-box of SOX8. In-vitro functional assays indicate that this mutation alters the biological activity of the protein. As an emerging body of evidence suggests that DSDs and infertility can have common etiologies, we also analyzed SOX8 in a cohort of infertile men (n = 274) and two independent cohorts of women with primary ovarian insufficiency (POI; n = 153 and n = 104). SOX8 mutations were found at increased frequency in oligozoospermic men (3.5%; p<0.05) and POI (5.06%; p=4.5x10-5) as compared to fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared to the wild-type protein. These data demonstrate that SOX8 plays an important role in human reproduction and SOX8 mutations contribute to a spectrum of phenotypes including 46,XY DSD, male infertility and 46,XX POI.

AB - SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but the role of SOX8 in humans is unknown. Here, we show that SOX8 is expressed in the somatic cells of the early developing gonad in the human and influences human sex-determination. We identified two individuals with 46,XY disorders/differences in sex development (DSD) and chromosomal rearrangements encompassing the SOX8 locus and a third individual with 46,XY DSD and a missense mutation in the HMG-box of SOX8. In-vitro functional assays indicate that this mutation alters the biological activity of the protein. As an emerging body of evidence suggests that DSDs and infertility can have common etiologies, we also analyzed SOX8 in a cohort of infertile men (n = 274) and two independent cohorts of women with primary ovarian insufficiency (POI; n = 153 and n = 104). SOX8 mutations were found at increased frequency in oligozoospermic men (3.5%; p<0.05) and POI (5.06%; p=4.5x10-5) as compared to fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared to the wild-type protein. These data demonstrate that SOX8 plays an important role in human reproduction and SOX8 mutations contribute to a spectrum of phenotypes including 46,XY DSD, male infertility and 46,XX POI.

KW - Journal article

KW - Phenotype

KW - Turner's syndrome

KW - Mutation

KW - Chromosome rearrangements

KW - Fertility

KW - Genes

U2 - 10.1093/hmg/ddy037

DO - 10.1093/hmg/ddy037

M3 - Article

C2 - 29373757

VL - 27

SP - 1228

EP - 1240

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 7

ER -