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

被引：55

作者：

Portnoi, Marie-France ^{[1
,2
]}

Dumargne, Marie-Charlotte ^{[3
]}

Rojo, Sandra ^{[3
]}

Witchel, Selma F. ^{[4
]}

Duncan, Andrew J. ^{[5
]}

Eozenou, Caroline ^{[3
]}

Bignon-Topalovic, Joelle ^{[3
]}

Yatsenko, Svetlana A. ^{[6
,7
,8
]}

Rajkovic, Aleksandar ^{[6
,7
,8
]}

Reyes-Mugica, Miguel ^{[6
,7
,8
]}

Almstrup, Kristian ^{[9
]}

Fusee, Leila

Srivastava, Yogesh ^{[10
,11
,12
]}

Chantot-Bastaraud, Sandra ^{[1
,2
]}

Hyon, Capucine ^{[1
]}

Louis-Sylvestre, Christine ^{[13
]}

Validire, Pierre ^{[14
]}

Pichard, Caroline de Malleray ^{[15
]}

Ravel, Celia ^{[16
]}

Christin-Maitre, Sophie ^{[2
,17
]}

Brauner, Raja ^{[18
,19
]}

Rossetti, Raffaella ^{[20
,21
,22
]}

Persani, Luca ^{[20
,21
,22
]}

Charreau, Eduardo H. ^{[23
,24
]}

Dain, Liliana ^{[23
,24
]}

Chiauzzi, Violeta A. ^{[23
,24
]}

Mazen, Inas ^{[25
]}

Rouba, Hassan ^{[26
]}

Schluth-Bolard, Caroline ^{[27
]}

MacGowan, Stuart ^{[28
]}

McLean, W. H. Irwin ^{[28
]}

Patin, Etienne ^{[29
]}

Rajpert-De Meyts, Ewa ^{[9
]}

Jauch, Ralf ^{[10
,11
,12
]}

Achermann, John C. ^{[5
]}

Siffroi, Jean-Pierre ^{[1
,2
]}

McElreavey, Ken ^{[3
]}

Bashamboo, Anu ^{[3
]}

机构：

[1] AP HP, Dept Genet Med, F-75012 Paris, France

[2] Univ Paris 06, UPMC, INSERM, Hop Armand Trousseau,UMR S933, F-75012 Paris, France

[3] CNRS, Inst Pasteur, Human Dev Genet, UMR 3738, F-75724 Paris, France

[4] UPMC, Childrens Hosp Pittsburgh, Div Pediat Endocrinol, Pittsburgh, PA 15224 USA

[5] UCL Great Ormond St Inst Child Hlth, Genet & Genom Med, London WC1N 1EH, England

[6] Univ Pittsburgh, Sch Med, Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA

[7] Univ Pittsburgh, Sch Med, Dept Human Genet, Pittsburgh, PA 15213 USA

[8] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA

[9] Rigshosp, Univ Dept Growth & Reprod, DK-2100 Copenhagen, Denmark

[10] Chinese Acad Sci, Drug Discovery Pipeline, Genome Regulat Lab, Guangzhou 510530, Guangdong, Peoples R China

[11] Chinese Acad Sci, Key Lab Regenerat Biol, Guangzhou 510530, Guangdong, Peoples R China

[12] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, South China Inst Stem Cell Biol & Regenerat Med, Guangdong Prov Key Lab Stem Cell & Regenerat Med, Guangzhou 510530, Guangdong, Peoples R China

[13] Inst Mutualiste Montsouris, Dept Mere Enfant, F-75014 Paris, France

[14] Inst Mutualiste Montsouris, Dept Anat Pathol, F-75014 Paris, France

[15] Hop Cochin, Serv Endocrinol, Paris, France

[16] CHU Rennes, Biol Reprod, F-35033 Rennes, France

[17] Hop St Antoine, Serv Endocrinol Diabetol & Endocrinoln Reprod, F-75012 Paris, France

[18] Univ Paris 05, F-75019 Paris, France

[19] Fdn Ophtalmol Adolphe Rothschild, Pediat Endocrinol Unit, F-75019 Paris, France

[20] Univ Milan, Dept Clin Sci & Community Hlth, I-20122 Milan, Italy

[21] IRCCS, Ist Auxol Italiano, Lab Endocrine & Metab Res, I-20149 Milan, Italy

[22] IRCCS, Ist Auxol Italiano, Div Endocrine & Metab Dis, I-20149 Milan, Italy

[23] Adm Nacl Lab Inst Salud ANLIS Dr Carlos G Malbran, Ctr Nacl Genet Med, C1428ADN, Buenos Aires, DF, Argentina

[24] Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, Dept Physiol, Consejo Nacl Invest Cient & Tecn,IBYME, C1428ADN, Buenos Aires, DF, Argentina

[25] Natl Res Ctr, Dept Clin Genet, Cairo 12622, Egypt

[26] Inst Pasteur Morocco, Human Genet Unit, Casablanca 20250, Morocco

[27] Hop Femme Mere Enfant, Genet Serv, F-69677 Bron, France

[28] Univ Dundee, Sch Life Sci, Ctr Dermatol & Genet Med, Dundee DD1 5EH, Scotland

[29] Inst Pasteur, Human Evolutionary Genet, F-75724 Paris, France

来源：

HUMAN MOLECULAR GENETICS | 2018年 / 27卷 / 07期

基金：

中国国家自然科学基金; 英国惠康基金;

关键词：

PRIMARY OVARIAN INSUFFICIENCY; SEX DETERMINATION; CAMPOMELIC DYSPLASIA; DELETION UPSTREAM; MALE-INFERTILITY; REVERSAL; NR5A1; SF1; DIFFERENTIATION; DUPLICATION;

D O I：

10.1093/hmg/ddy037

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 x 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.

引用

页码：1228 / 1240

页数：13