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
SN - 0964-6906
VL - 27
SP - 1228
EP - 1240
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 7
ER -