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, Svetlana A Yatsenko, Aleksandar Rajkovic, Miguel Reyes-Mugica, Kristian Almstrup, Leila 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

Research output: Contribution to journalArticle

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 analysed 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 = 4.5 × 10-5) as compared with fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared with 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
DOIs
Publication statusPublished - Apr 1 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

  • 46, XX Disorders of Sex Development/genetics
  • Adolescent
  • Child
  • Disorder of Sex Development, 46,XY/genetics
  • Female
  • Humans
  • Male
  • Mutation, Missense
  • Oligospermia/genetics
  • Primary Ovarian Insufficiency/genetics
  • SOXE Transcription Factors/genetics

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

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, Svetlana A; Rajkovic, Aleksandar; Reyes-Mugica, Miguel; Almstrup, Kristian; Fusee, Leila; 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.

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

Research output: Contribution to journalArticle

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
Portnoi, Marie-France ; Dumargne, Marie-Charlotte ; Rojo, Sandra ; Witchel, Selma F ; Duncan, Andrew J ; Eozenou, Caroline ; Bignon-Topalovic, Joelle ; Yatsenko, Svetlana A ; Rajkovic, Aleksandar ; Reyes-Mugica, Miguel ; Almstrup, Kristian ; Fusee, Leila ; 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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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, Svetlana A

AU - Rajkovic, Aleksandar

AU - Reyes-Mugica, Miguel

AU - Almstrup, Kristian

AU - Fusee, Leila

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

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 analysed 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 = 4.5 × 10-5) as compared with fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared with 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 analysed 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 = 4.5 × 10-5) as compared with fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared with 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 - 46, XX Disorders of Sex Development/genetics

KW - Adolescent

KW - Child

KW - Disorder of Sex Development, 46,XY/genetics

KW - Female

KW - Humans

KW - Male

KW - Mutation, Missense

KW - Oligospermia/genetics

KW - Primary Ovarian Insufficiency/genetics

KW - SOXE Transcription Factors/genetics

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 -