ArticleGenetics in medicine : official journal of the American College of Medical Genetics2017
NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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51 citing papers in PubMed, 139 citations in OpenAlex.
- Checking assumptions: advancing the analysis of sex and gender in health sciences.Biology of sex differences · 2026Review
- Clinical features and genetic characteristics of ovotesticular disorders of sex development: 24 cases from a single center.World journal of urology · 2025Article
- Comparative Transcriptomic Analysis of Male and Female Gonads inAnimals : an open access journal from MDPI · 2025Article
- Neurocognitive function in males with 46,XX testicular difference of sex development.Orphanet journal of rare diseases · 2025Article
- Computational tracking of cell origins using CellSexID from single-cell transcriptomes.Cell reports methods · 2025Article
- Phenotypic spectrum and long-term outcomes of patients with 46,XX disorders of sex development.Annals of pediatric endocrinology & metabolism · 2025Article
- Clinical spectrum and molecular basis in 19 Chinese patients with 46, XY disorder of sexual development caused by NR5A1 mutations.Orphanet journal of rare diseases · 2024Article
- Population-Based Study of Rare Coding Variants inJournal of the Endocrine Society · 2024Article
- A NovelJournal of pediatric genetics · 2024Article
- Evidence for NR2F2/COUP-TFII involvement in human testis development.Scientific reports · 2024Article
- Role ofCurrent issues in molecular biology · 2024Review
- Reprograming skin fibroblasts into Sertoli cells: a patient-specific tool to understand effects of genetic variants on gonadal development.Biology of sex differences · 2024Article
- 46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes.Frontiers in endocrinology · 2024Review
- Diagnosis and management of non-CAH 46,XX disorders/differences in sex development.Frontiers in endocrinology · 2024Review
- Phenotype-Genotype Discordance and a Case of a Disorder of Sexual Differentiation.Case reports in genetics · 2024Article
- Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development.EBioMedicine · 2024Article
- Testicular differentiation in 46,XX DSD: an overview of genetic causes.Frontiers in endocrinology · 2024Review
- A Novel Variant inJCEM case reports · 2023Article
- Genetic control of typical and atypical sex development.Nature reviews. Urology · 2023Review
- Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development.Biomolecules · 2023Review
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeWe 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).
methodsWhole-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.
resultsWe 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.
conclusionsWe 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.
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