NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development

Dorien Baetens; Hans Stoop; Frank Peelman; Anne-Laure Todeschini; Toon Rosseel; Frauke Coppieters; Reiner A Veitia; Leendert H J Looijenga; Elfride De Baere; Martine Cools

doi:10.1038/gim.2016.118

NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development

Dorien Baetens, Hans Stoop, Frank Peelman, Anne-Laure Todeschini, Toon Rosseel, Frauke Coppieters, Reiner A Veitia, Leendert H J Looijenga, Elfride De Baere, Martine Cools

Research output: Contribution to journal › Article › peer-review

94 Citations (Scopus)

Abstract

PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD).

METHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq.

RESULTS: We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed.

CONCLUSIONS: We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad.Genet Med 19 4, 367-376.

Original language	English
Pages (from-to)	367-376
Number of pages	10
Journal	Genetics in medicine : official journal of the American College of Medical Genetics
Volume	19
Issue number	4
DOIs	https://doi.org/10.1038/gim.2016.118
Publication status	Published - Apr 2017
Externally published	Yes

Keywords

DNA-Binding Proteins/genetics
Female
Gene Expression Profiling/methods
Genetic Predisposition to Disease
Haplotypes
Humans
Male
Models, Molecular
Mutation, Missense
Nuclear Proteins/genetics
Ovary/metabolism
Ovotesticular Disorders of Sex Development/genetics
Pedigree
Polymorphism, Single Nucleotide
Sequence Analysis, RNA/methods
Steroidogenic Factor 1/chemistry
Testis/metabolism
Transcription Factors/genetics
Up-Regulation
Whole Exome Sequencing/methods
Young Adult

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10.1038/gim.2016.118

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Baetens, D., Stoop, H., Peelman, F., Todeschini, A.-L., Rosseel, T., Coppieters, F., Veitia, R. A., Looijenga, L. H. J., De Baere, E., & Cools, M. (2017). NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development. Genetics in medicine : official journal of the American College of Medical Genetics, 19(4), 367-376. https://doi.org/10.1038/gim.2016.118

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title = "NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development",

abstract = "PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD).METHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq.RESULTS: We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed.CONCLUSIONS: We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad.Genet Med 19 4, 367-376.",

keywords = "DNA-Binding Proteins/genetics, Female, Gene Expression Profiling/methods, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Models, Molecular, Mutation, Missense, Nuclear Proteins/genetics, Ovary/metabolism, Ovotesticular Disorders of Sex Development/genetics, Pedigree, Polymorphism, Single Nucleotide, Sequence Analysis, RNA/methods, Steroidogenic Factor 1/chemistry, Testis/metabolism, Transcription Factors/genetics, Up-Regulation, Whole Exome Sequencing/methods, Young Adult",

author = "Dorien Baetens and Hans Stoop and Frank Peelman and Anne-Laure Todeschini and Toon Rosseel and Frauke Coppieters and Veitia, {Reiner A} and Looijenga, {Leendert H J} and {De Baere}, Elfride and Martine Cools",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2016.",

year = "2017",

month = apr,

doi = "10.1038/gim.2016.118",

language = "English",

volume = "19",

pages = "367--376",

journal = "Genetics in medicine : official journal of the American College of Medical Genetics",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "4",

}

Baetens, D, Stoop, H, Peelman, F, Todeschini, A-L, Rosseel, T, Coppieters, F, Veitia, RA, Looijenga, LHJ, De Baere, E & Cools, M 2017, 'NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development', Genetics in medicine : official journal of the American College of Medical Genetics, vol. 19, no. 4, pp. 367-376. https://doi.org/10.1038/gim.2016.118

TY - JOUR

T1 - NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development

AU - Baetens, Dorien

AU - Stoop, Hans

AU - Peelman, Frank

AU - Todeschini, Anne-Laure

AU - Rosseel, Toon

AU - Coppieters, Frauke

AU - Veitia, Reiner A

AU - Looijenga, Leendert H J

AU - De Baere, Elfride

AU - Cools, Martine

N1 - Publisher Copyright: © The Author(s) 2016.

PY - 2017/4

Y1 - 2017/4

N2 - PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD).METHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq.RESULTS: We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed.CONCLUSIONS: We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad.Genet Med 19 4, 367-376.

AB - PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD).METHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq.RESULTS: We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed.CONCLUSIONS: We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad.Genet Med 19 4, 367-376.

KW - DNA-Binding Proteins/genetics

KW - Female

KW - Gene Expression Profiling/methods

KW - Genetic Predisposition to Disease

KW - Haplotypes

KW - Humans

KW - Male

KW - Models, Molecular

KW - Mutation, Missense

KW - Nuclear Proteins/genetics

KW - Ovary/metabolism

KW - Ovotesticular Disorders of Sex Development/genetics

KW - Pedigree

KW - Polymorphism, Single Nucleotide

KW - Sequence Analysis, RNA/methods

KW - Steroidogenic Factor 1/chemistry

KW - Testis/metabolism

KW - Transcription Factors/genetics

KW - Up-Regulation

KW - Whole Exome Sequencing/methods

KW - Young Adult

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U2 - 10.1038/gim.2016.118

DO - 10.1038/gim.2016.118

M3 - Article

C2 - 27490115

SN - 1098-3600

VL - 19

SP - 367

EP - 376

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

IS - 4

ER -

NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development

Abstract

Keywords

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