Portnoi, M-F;
Dumargne, M-C;
Rojo, S;
Witchel, SF;
Duncan, AJ;
Eozenou, C;
Bignon-Topalovic, J;
... Bashamboo, A; + view all
(2018)
Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies.
Human Molecular Genetics
, 27
(7)
pp. 1228-1240.
10.1093/hmg/ddy037.
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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.
| Type: | Article |
|---|---|
| Title: | Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/hmg/ddy037 |
| Publisher version: | http://doi.org/10.1093/hmg/ddy037 |
| Language: | English |
| Additional information: | © The Author 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Phenotype; turner's syndrome; mutation chromosome rearrangements; fertility; genes; gonads; infertility; male infertility; missense mutation; reproductive physiological process; sex determination (analysis); mice; transcription factor; karyotype 46, xx; sexual development; somatic cell; mutant proteins; sox9 gene |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10043563 |
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