Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development
Identifieur interne : 006271 ( Main/Exploration ); précédent : 006270; suivant : 006272Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development
Auteurs : Sabina Benko [France] ; Christopher T. Gordon [France] ; Delphine Mallet [France] ; Rajini Sreenivasan [Australie] ; Christel Thauvin-Robinet [France] ; Atle Brendehaug [Norvège] ; Sophie Thomas [France] ; Ove Bruland [Norvège] ; Michel David [France] ; Marc Nicolino [France] ; Audrey Labalme [France] ; Damien Sanlaville [France] ; Patrick Callier ; Valerie Malan [France] ; Frédéric Huet ; Anders Molven [Norvège] ; Frédérique Dijoud [France] ; Arnold Munnich [France] ; Laurence Faivre [France] ; Jeanne Amiel [France] ; Vincent Harley [Australie] ; Gunnar Houge [France, Norvège] ; Yves Morel [France] ; Stanislas Lyonnet [France]Source :
- Journal of Medical Genetics [ 0022-2593 ] ; 2011-12.
Descripteurs français
- Pascal (Inist)
- Wicri :
English descriptors
- KwdEn :
- Arnold munnich, Asymmetric scrotum, Bergen, Bilateral gonadectomy, Bipotential gonad, Campomelic dysplasia, Cell lineage, Chromatin, Chromatin environment, Chromosome, Copy number gains, Copy number variation, Copy number variation mapping, Copy number variations, Deletion, Development, Disruption, Distance, Dsd1, Dsd1 patient, Dsd2, Dsd2 case, Dsd2 family, Dsd3, Dsd3 duplication, Dsd3 patients, Dsd4, Dsd4 deletion, Dsd4 family, Dsd4 index cases, Duplication, Dysplasia, Enhancer, Enhancer activity, Fallopian tube, Familial case, Female phenotype, Feminising genitoplasty, Gene desert, Genet, Genetic basis, Genetics, Genomic, Genomic alterations, Genomic variants, Gonad, Gonadal, Gonadal development, Gonadal dysgenesis, Gonadal sox9 expression, Gunnar houge, Gure, Haukeland university hospital, Healthy father, Hormonal data, Hospices civils, Human, Index patient, Inserm hopital malades, Jeanne amiel, Junction fragment, Large duplications, Laurence faivre, Locus, Long distance, Metaphase fish, Negative patients, Normal males, Normal values, Oligonucleotide arrays, Perineal hypospadias, Phenotype, Pierre robin sequence, Proximal sox9 gene desert, Revsex, Revsex region, Right gonad, Sabina benko, Serum testosterone, Sex, Skeletal dysplasia, Sox9, Sox9 centromeric gene desert, Sox9 expression, Sox9 gene, Sox9 gonadal expression, Sox9 locus, Sox9 promoter, Sox9 transcription, Stanislas lyonnet, Streak gonad, Tesco, Testicular, Testicular development, Testicular dysgenesis, Testis, Transgenic mice, Translocation, Value range, Vincent harley, Yves morel.
- Teeft :
- Arnold munnich, Asymmetric scrotum, Bergen, Bilateral gonadectomy, Bipotential gonad, Campomelic dysplasia, Cell lineage, Chromatin, Chromatin environment, Chromosome, Copy number gains, Copy number variation, Copy number variation mapping, Copy number variations, Deletion, Dsd1, Dsd1 patient, Dsd2, Dsd2 case, Dsd2 family, Dsd3, Dsd3 duplication, Dsd3 patients, Dsd4, Dsd4 deletion, Dsd4 family, Dsd4 index cases, Duplication, Dysplasia, Enhancer, Enhancer activity, Fallopian tube, Familial case, Female phenotype, Feminising genitoplasty, Gene desert, Genet, Genetic basis, Genomic, Genomic alterations, Genomic variants, Gonad, Gonadal, Gonadal development, Gonadal dysgenesis, Gonadal sox9 expression, Gunnar houge, Gure, Haukeland university hospital, Healthy father, Hormonal data, Hospices civils, Index patient, Inserm hopital malades, Jeanne amiel, Junction fragment, Large duplications, Laurence faivre, Locus, Long distance, Metaphase fish, Negative patients, Normal males, Normal values, Oligonucleotide arrays, Perineal hypospadias, Phenotype, Pierre robin sequence, Proximal sox9 gene desert, Revsex, Revsex region, Right gonad, Sabina benko, Serum testosterone, Skeletal dysplasia, Sox9, Sox9 centromeric gene desert, Sox9 expression, Sox9 gene, Sox9 gonadal expression, Sox9 locus, Sox9 promoter, Sox9 transcription, Stanislas lyonnet, Streak gonad, Tesco, Testicular, Testicular development, Testicular dysgenesis, Testis, Transgenic mice, Translocation, Value range, Vincent harley, Yves morel.
Abstract
Background The early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off. Results Through copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517–595 kb upstream of the SOX9 promoter. Conclusions These data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.
Url:
DOI: 10.1136/jmedgenet-2011-100255
Affiliations:
- Australie, France, Norvège
- Bourgogne, Bourgogne-Franche-Comté, Victoria (État), Île-de-France
- Dijon, Melbourne, Paris
- Université Paris-Descartes, Université de Melbourne
Links toward previous steps (curation, corpus...)
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- to stream Main, to step Curation: 006271
Le document en format XML
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Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Thauvin Robinet, Christel" sort="Thauvin Robinet, Christel" uniqKey="Thauvin Robinet C" first="Christel" last="Thauvin-Robinet">Christel Thauvin-Robinet</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Centre de Génétique, Hôpital d'Enfants, Dijon</wicri:regionArea><placeName><region type="region">Bourgogne-Franche-Comté</region><region type="old region">Bourgogne</region><settlement type="city">Dijon</settlement></placeName></affiliation></author><author><name sortKey="Brendehaug, Atle" sort="Brendehaug, Atle" uniqKey="Brendehaug A" first="Atle" last="Brendehaug">Atle Brendehaug</name><affiliation wicri:level="1"><country xml:lang="fr">Norvège</country><wicri:regionArea>Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Thomas, Sophie" sort="Thomas, Sophie" uniqKey="Thomas S" first="Sophie" last="Thomas">Sophie Thomas</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>INSERM U-781, Hôpital Necker-Enfants Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">France</country><wicri:regionArea>Université Paris Descartes, Faculté de Médecine, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation></author><author><name sortKey="Bruland, Ove" sort="Bruland, Ove" uniqKey="Bruland O" first="Ove" last="Bruland">Ove Bruland</name><affiliation wicri:level="1"><country xml:lang="fr">Norvège</country><wicri:regionArea>Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="David, Michel" sort="David, Michel" uniqKey="David M" first="Michel" last="David">Michel David</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Endocrinologie Pédiatrique, HFME, Hospices Civils de Lyon, Bron</wicri:regionArea><wicri:noRegion>Bron</wicri:noRegion><wicri:noRegion>Bron</wicri:noRegion></affiliation></author><author><name sortKey="Nicolino, Marc" sort="Nicolino, Marc" uniqKey="Nicolino M" first="Marc" last="Nicolino">Marc Nicolino</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Endocrinologie Pédiatrique, HFME, Hospices Civils de Lyon, Bron</wicri:regionArea><wicri:noRegion>Bron</wicri:noRegion><wicri:noRegion>Bron</wicri:noRegion></affiliation></author><author><name sortKey="Labalme, Audrey" sort="Labalme, Audrey" uniqKey="Labalme A" first="Audrey" last="Labalme">Audrey Labalme</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Cytogénétique, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron</wicri:regionArea><wicri:noRegion>Bron</wicri:noRegion><wicri:noRegion>Bron</wicri:noRegion></affiliation></author><author><name sortKey="Sanlaville, Damien" sort="Sanlaville, Damien" uniqKey="Sanlaville D" first="Damien" last="Sanlaville">Damien Sanlaville</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Cytogénétique, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron</wicri:regionArea><wicri:noRegion>Bron</wicri:noRegion><wicri:noRegion>Bron</wicri:noRegion></affiliation></author><author><name sortKey="Callier, Patrick" sort="Callier, Patrick" uniqKey="Callier P" first="Patrick" last="Callier">Patrick Callier</name><affiliation><wicri:noCountry code="subField">Dijon</wicri:noCountry></affiliation></author><author><name sortKey="Malan, Valerie" sort="Malan, Valerie" uniqKey="Malan V" first="Valerie" last="Malan">Valerie Malan</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>AP-HP, Service d'Histo-embryo-cytogénétique, Hôpital Necker-Enfants Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Huet, Frederic" sort="Huet, Frederic" uniqKey="Huet F" first="Frédéric" last="Huet">Frédéric Huet</name><affiliation><wicri:noCountry code="subField">Dijon</wicri:noCountry></affiliation></author><author><name sortKey="Molven, Anders" sort="Molven, Anders" uniqKey="Molven A" first="Anders" last="Molven">Anders Molven</name><affiliation wicri:level="1"><country xml:lang="fr">Norvège</country><wicri:regionArea>The Gade Institute, University of Bergen, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Pathology, Haukeland University Hospital, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Dijoud, Frederique" sort="Dijoud, Frederique" uniqKey="Dijoud F" first="Frédérique" last="Dijoud">Frédérique Dijoud</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Service d'anatomopathologie, Centre de Biologie Est, Hospices Civils de Lyon, Bron</wicri:regionArea><wicri:noRegion>Bron</wicri:noRegion><wicri:noRegion>Bron</wicri:noRegion></affiliation></author><author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>INSERM U-781, Hôpital Necker-Enfants Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">France</country><wicri:regionArea>Université Paris Descartes, Faculté de Médecine, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>AP-HP, Département de Génétique, Hôpital Necker-Enfants Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Faivre, Laurence" sort="Faivre, Laurence" uniqKey="Faivre L" first="Laurence" last="Faivre">Laurence Faivre</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Centre de Génétique, Hôpital d'Enfants, Dijon</wicri:regionArea><placeName><region type="region">Bourgogne-Franche-Comté</region><region type="old region">Bourgogne</region><settlement type="city">Dijon</settlement></placeName></affiliation></author><author><name sortKey="Amiel, Jeanne" sort="Amiel, Jeanne" uniqKey="Amiel J" first="Jeanne" last="Amiel">Jeanne Amiel</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>INSERM U-781, Hôpital Necker-Enfants Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">France</country><wicri:regionArea>Université Paris Descartes, Faculté de Médecine, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>AP-HP, Département de Génétique, Hôpital Necker-Enfants Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Harley, Vincent" sort="Harley, Vincent" uniqKey="Harley V" first="Vincent" last="Harley">Vincent Harley</name><affiliation wicri:level="1"><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Genetics and Development, Prince Henry's Institute of Medical Research, Monash Medical Centre, Clayton</wicri:regionArea><wicri:noRegion>Clayton</wicri:noRegion></affiliation></author><author><name sortKey="Houge, Gunnar" sort="Houge, Gunnar" uniqKey="Houge G" first="Gunnar" last="Houge">Gunnar Houge</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Centre de Génétique, Hôpital d'Enfants, Dijon</wicri:regionArea><placeName><region type="region">Bourgogne-Franche-Comté</region><region type="old region">Bourgogne</region><settlement type="city">Dijon</settlement></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Clinical Medicine, University of Bergen, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Morel, Yves" sort="Morel, Yves" uniqKey="Morel Y" first="Yves" last="Morel">Yves Morel</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Endocrinologie Moléculaire et Maladies Rares, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron</wicri:regionArea><wicri:noRegion>Bron</wicri:noRegion><wicri:noRegion>Bron</wicri:noRegion></affiliation></author><author><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>INSERM U-781, Hôpital Necker-Enfants Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">France</country><wicri:regionArea>Université Paris Descartes, Faculté de Médecine, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Service d'anatomopathologie, Centre de Biologie Est, Hospices Civils de Lyon, Bron</wicri:regionArea><wicri:noRegion>Bron</wicri:noRegion><wicri:noRegion>Bron</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">France</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Medical Genetics</title><title level="j" type="abbrev">J Med Genet</title><idno type="ISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2011-12">2011-12</date><biblScope unit="volume">48</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="825">825</biblScope></imprint><idno type="ISSN">0022-2593</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2593</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Arnold munnich</term><term>Asymmetric scrotum</term><term>Bergen</term><term>Bilateral gonadectomy</term><term>Bipotential gonad</term><term>Campomelic dysplasia</term><term>Cell lineage</term><term>Chromatin</term><term>Chromatin environment</term><term>Chromosome</term><term>Copy number gains</term><term>Copy number variation</term><term>Copy number variation mapping</term><term>Copy number variations</term><term>Deletion</term><term>Development</term><term>Disruption</term><term>Distance</term><term>Dsd1</term><term>Dsd1 patient</term><term>Dsd2</term><term>Dsd2 case</term><term>Dsd2 family</term><term>Dsd3</term><term>Dsd3 duplication</term><term>Dsd3 patients</term><term>Dsd4</term><term>Dsd4 deletion</term><term>Dsd4 family</term><term>Dsd4 index cases</term><term>Duplication</term><term>Dysplasia</term><term>Enhancer</term><term>Enhancer activity</term><term>Fallopian tube</term><term>Familial case</term><term>Female phenotype</term><term>Feminising genitoplasty</term><term>Gene desert</term><term>Genet</term><term>Genetic basis</term><term>Genetics</term><term>Genomic</term><term>Genomic alterations</term><term>Genomic variants</term><term>Gonad</term><term>Gonadal</term><term>Gonadal development</term><term>Gonadal dysgenesis</term><term>Gonadal sox9 expression</term><term>Gunnar houge</term><term>Gure</term><term>Haukeland university hospital</term><term>Healthy father</term><term>Hormonal data</term><term>Hospices civils</term><term>Human</term><term>Index patient</term><term>Inserm hopital malades</term><term>Jeanne amiel</term><term>Junction fragment</term><term>Large duplications</term><term>Laurence faivre</term><term>Locus</term><term>Long distance</term><term>Metaphase fish</term><term>Negative patients</term><term>Normal males</term><term>Normal values</term><term>Oligonucleotide arrays</term><term>Perineal hypospadias</term><term>Phenotype</term><term>Pierre robin sequence</term><term>Proximal sox9 gene desert</term><term>Revsex</term><term>Revsex region</term><term>Right gonad</term><term>Sabina benko</term><term>Serum testosterone</term><term>Sex</term><term>Skeletal dysplasia</term><term>Sox9</term><term>Sox9 centromeric gene desert</term><term>Sox9 expression</term><term>Sox9 gene</term><term>Sox9 gonadal expression</term><term>Sox9 locus</term><term>Sox9 promoter</term><term>Sox9 transcription</term><term>Stanislas lyonnet</term><term>Streak gonad</term><term>Tesco</term><term>Testicular</term><term>Testicular development</term><term>Testicular dysgenesis</term><term>Testis</term><term>Transgenic mice</term><term>Translocation</term><term>Value range</term><term>Vincent harley</term><term>Yves morel</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Disruption</term><term>Distance</term><term>Développement</term><term>Génétique</term><term>Homme</term><term>Sexe</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Arnold munnich</term><term>Asymmetric scrotum</term><term>Bergen</term><term>Bilateral gonadectomy</term><term>Bipotential gonad</term><term>Campomelic dysplasia</term><term>Cell lineage</term><term>Chromatin</term><term>Chromatin environment</term><term>Chromosome</term><term>Copy number gains</term><term>Copy number variation</term><term>Copy number variation mapping</term><term>Copy number variations</term><term>Deletion</term><term>Dsd1</term><term>Dsd1 patient</term><term>Dsd2</term><term>Dsd2 case</term><term>Dsd2 family</term><term>Dsd3</term><term>Dsd3 duplication</term><term>Dsd3 patients</term><term>Dsd4</term><term>Dsd4 deletion</term><term>Dsd4 family</term><term>Dsd4 index cases</term><term>Duplication</term><term>Dysplasia</term><term>Enhancer</term><term>Enhancer activity</term><term>Fallopian tube</term><term>Familial case</term><term>Female phenotype</term><term>Feminising genitoplasty</term><term>Gene desert</term><term>Genet</term><term>Genetic basis</term><term>Genomic</term><term>Genomic alterations</term><term>Genomic variants</term><term>Gonad</term><term>Gonadal</term><term>Gonadal development</term><term>Gonadal dysgenesis</term><term>Gonadal sox9 expression</term><term>Gunnar houge</term><term>Gure</term><term>Haukeland university hospital</term><term>Healthy father</term><term>Hormonal data</term><term>Hospices civils</term><term>Index patient</term><term>Inserm hopital malades</term><term>Jeanne amiel</term><term>Junction fragment</term><term>Large duplications</term><term>Laurence faivre</term><term>Locus</term><term>Long distance</term><term>Metaphase fish</term><term>Negative patients</term><term>Normal males</term><term>Normal values</term><term>Oligonucleotide arrays</term><term>Perineal hypospadias</term><term>Phenotype</term><term>Pierre robin sequence</term><term>Proximal sox9 gene desert</term><term>Revsex</term><term>Revsex region</term><term>Right gonad</term><term>Sabina benko</term><term>Serum testosterone</term><term>Skeletal dysplasia</term><term>Sox9</term><term>Sox9 centromeric gene desert</term><term>Sox9 expression</term><term>Sox9 gene</term><term>Sox9 gonadal expression</term><term>Sox9 locus</term><term>Sox9 promoter</term><term>Sox9 transcription</term><term>Stanislas lyonnet</term><term>Streak gonad</term><term>Tesco</term><term>Testicular</term><term>Testicular development</term><term>Testicular dysgenesis</term><term>Testis</term><term>Transgenic mice</term><term>Translocation</term><term>Value range</term><term>Vincent harley</term><term>Yves morel</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term><term>Homme</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Background The early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off. Results Through copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517–595 kb upstream of the SOX9 promoter. Conclusions These data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Norvège</li></country><region><li>Bourgogne</li><li>Bourgogne-Franche-Comté</li><li>Victoria (État)</li><li>Île-de-France</li></region><settlement><li>Dijon</li><li>Melbourne</li><li>Paris</li></settlement><orgName><li>Université Paris-Descartes</li><li>Université de Melbourne</li></orgName></list><tree><noCountry><name sortKey="Callier, Patrick" sort="Callier, Patrick" uniqKey="Callier P" first="Patrick" last="Callier">Patrick Callier</name><name sortKey="Huet, Frederic" sort="Huet, Frederic" uniqKey="Huet F" first="Frédéric" last="Huet">Frédéric Huet</name></noCountry><country name="France"><region name="Île-de-France"><name sortKey="Benko, Sabina" sort="Benko, Sabina" uniqKey="Benko S" first="Sabina" last="Benko">Sabina Benko</name></region><name sortKey="Amiel, Jeanne" sort="Amiel, Jeanne" uniqKey="Amiel J" first="Jeanne" last="Amiel">Jeanne Amiel</name><name sortKey="Amiel, Jeanne" sort="Amiel, Jeanne" uniqKey="Amiel J" first="Jeanne" last="Amiel">Jeanne Amiel</name><name sortKey="Amiel, Jeanne" sort="Amiel, Jeanne" uniqKey="Amiel J" first="Jeanne" last="Amiel">Jeanne Amiel</name><name sortKey="Benko, Sabina" sort="Benko, Sabina" uniqKey="Benko S" first="Sabina" last="Benko">Sabina Benko</name><name sortKey="David, Michel" sort="David, Michel" uniqKey="David M" first="Michel" last="David">Michel David</name><name sortKey="Dijoud, Frederique" sort="Dijoud, Frederique" uniqKey="Dijoud F" first="Frédérique" last="Dijoud">Frédérique Dijoud</name><name sortKey="Faivre, Laurence" sort="Faivre, Laurence" uniqKey="Faivre L" first="Laurence" last="Faivre">Laurence Faivre</name><name sortKey="Gordon, Christopher T" sort="Gordon, Christopher T" uniqKey="Gordon C" first="Christopher T" last="Gordon">Christopher T. Gordon</name><name sortKey="Gordon, Christopher T" sort="Gordon, Christopher T" uniqKey="Gordon C" first="Christopher T" last="Gordon">Christopher T. Gordon</name><name sortKey="Houge, Gunnar" sort="Houge, Gunnar" uniqKey="Houge G" first="Gunnar" last="Houge">Gunnar Houge</name><name sortKey="Labalme, Audrey" sort="Labalme, Audrey" uniqKey="Labalme A" first="Audrey" last="Labalme">Audrey Labalme</name><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name><name sortKey="Malan, Valerie" sort="Malan, Valerie" uniqKey="Malan V" first="Valerie" last="Malan">Valerie Malan</name><name sortKey="Mallet, Delphine" sort="Mallet, Delphine" uniqKey="Mallet D" first="Delphine" last="Mallet">Delphine Mallet</name><name sortKey="Morel, Yves" sort="Morel, Yves" uniqKey="Morel Y" first="Yves" last="Morel">Yves Morel</name><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><name sortKey="Nicolino, Marc" sort="Nicolino, Marc" uniqKey="Nicolino M" first="Marc" last="Nicolino">Marc Nicolino</name><name sortKey="Sanlaville, Damien" sort="Sanlaville, Damien" uniqKey="Sanlaville D" first="Damien" last="Sanlaville">Damien Sanlaville</name><name sortKey="Thauvin Robinet, Christel" sort="Thauvin Robinet, Christel" uniqKey="Thauvin Robinet C" first="Christel" last="Thauvin-Robinet">Christel Thauvin-Robinet</name><name sortKey="Thomas, Sophie" sort="Thomas, Sophie" uniqKey="Thomas S" first="Sophie" last="Thomas">Sophie Thomas</name><name sortKey="Thomas, Sophie" sort="Thomas, Sophie" uniqKey="Thomas S" first="Sophie" last="Thomas">Sophie Thomas</name></country><country name="Australie"><noRegion><name sortKey="Sreenivasan, Rajini" sort="Sreenivasan, Rajini" uniqKey="Sreenivasan R" first="Rajini" last="Sreenivasan">Rajini Sreenivasan</name></noRegion><name sortKey="Harley, Vincent" sort="Harley, Vincent" uniqKey="Harley V" first="Vincent" last="Harley">Vincent Harley</name><name sortKey="Sreenivasan, Rajini" sort="Sreenivasan, Rajini" uniqKey="Sreenivasan R" first="Rajini" last="Sreenivasan">Rajini Sreenivasan</name></country><country name="Norvège"><noRegion><name sortKey="Brendehaug, Atle" sort="Brendehaug, Atle" uniqKey="Brendehaug A" first="Atle" last="Brendehaug">Atle Brendehaug</name></noRegion><name sortKey="Bruland, Ove" sort="Bruland, Ove" uniqKey="Bruland O" first="Ove" last="Bruland">Ove Bruland</name><name sortKey="Houge, Gunnar" sort="Houge, Gunnar" uniqKey="Houge G" first="Gunnar" last="Houge">Gunnar Houge</name><name sortKey="Molven, Anders" sort="Molven, Anders" uniqKey="Molven A" first="Anders" last="Molven">Anders Molven</name><name sortKey="Molven, Anders" sort="Molven, Anders" uniqKey="Molven A" first="Anders" last="Molven">Anders Molven</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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