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

(2017) GENETICS IN MEDICINE. 19(4). p.367-376
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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 MAMLDI, 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 NR5A 1, 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 NR5A 1 in testis differentiation in the XX gonad.
Keywords
ovotesticular DSD, NR5A1, testicular DSD, XX DSD, 46, gonadal development, STEROIDOGENIC FACTOR-1, TRUE HERMAPHRODITISM, XX MALE, ADRENAL INSUFFICIENCY, OVARIAN INSUFFICIENCY, GONADAL DEVELOPMENT, PARTIAL DUPLICATION, NUCLEAR RECEPTOR, RNA-SEQ, MUTATIONS

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Citation

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Chicago
Baetens, Dorien, Hans Stoop, Frank Peelman, Anne-Laure Todeschini, Toon Rosseel, Frauke Coppieters, Reiner Veitia, Leendert Looijenga, Elfride De Baere, and Martine Cools. 2017. “NR5A1 Is a Novel Disease Gene for 46,XX Testicular and Ovotesticular Disorders of Sex Development.” Genetics in Medicine 19 (4): 367–376.
APA
Baetens, Dorien, Stoop, H., Peelman, F., Todeschini, A.-L., Rosseel, T., Coppieters, F., Veitia, R., et al. (2017). NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development. GENETICS IN MEDICINE, 19(4), 367–376.
Vancouver
1.
Baetens D, Stoop H, Peelman F, Todeschini A-L, Rosseel T, Coppieters F, et al. NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development. GENETICS IN MEDICINE. 2017;19(4):367–76.
MLA
Baetens, Dorien, Hans Stoop, Frank Peelman, et al. “NR5A1 Is a Novel Disease Gene for 46,XX Testicular and Ovotesticular Disorders of Sex Development.” GENETICS IN MEDICINE 19.4 (2017): 367–376. Print.
@article{8119627,
  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{\textrangle}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 MAMLDI, 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 NR5A 1, 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 NR5A 1 in testis differentiation in the XX gonad.},
  author       = {Baetens, Dorien and Stoop, Hans and Peelman, Frank and Todeschini, Anne-Laure and Rosseel, Toon and Coppieters, Frauke and Veitia, Reiner and Looijenga, Leendert and De Baere, Elfride and Cools, Martine},
  issn         = {1098-3600},
  journal      = {GENETICS IN MEDICINE},
  keyword      = {ovotesticular DSD,NR5A1,testicular DSD,XX DSD,46,gonadal development,STEROIDOGENIC FACTOR-1,TRUE HERMAPHRODITISM,XX MALE,ADRENAL INSUFFICIENCY,OVARIAN INSUFFICIENCY,GONADAL DEVELOPMENT,PARTIAL DUPLICATION,NUCLEAR RECEPTOR,RNA-SEQ,MUTATIONS},
  language     = {eng},
  number       = {4},
  pages        = {367--376},
  title        = {NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development},
  url          = {http://dx.doi.org/10.1038/gim.2016.118},
  volume       = {19},
  year         = {2017},
}

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