Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer

Rajini Sreenivasan, Louisa Mabel Ludbrook, Brett Daniel Fisher, Faustine Declosmenil, Kevin C. Knower, Brittany Marie Croft, Anthony Daniel Bird, Janelle Ryan, Anu Bashamboo, Andrew Sinclair, Peter Koopman, Ken McElreavey, Francis Poulat, Vincent Russel Harley

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)


Nuclear receptor subfamily 5 group A member 1/Steroidogenic factor 1 (NR5A1; SF-1; Ad4BP) mutations cause 46,XY disorders of sex development (DSD), with phenotypes ranging from developmentally mild (e.g., hypospadias) to severe (e.g., complete gonadal dysgenesis). The molecular mechanism underlying this spectrum is unclear. During sex determination, SF-1 regulates SOX9 (SRY [sex determining region Y]-box 9) expression. We hypothesized that SF-1 mutations in 46,XY DSD patients affect SOX9 expression via the Testis-specific Enhancer of Sox9 core element, TESCO. Our objective was to assess the ability of 20 SF-1 mutants found in 46,XY DSD patients to activate TESCO. Patient DNA was sequenced for SF-1 mutations and mutant SF-1 proteins were examined for transcriptional activity, protein expression, sub-cellular localization and in silico structural defects. Fifteen of the 20 mutants showed reduced SF-1 activation on TESCO, 11 with atypical sub-cellular localization. Fourteen SF-1 mutants were predicted in silico to alter DNA, ligand or cofactor interactions. Our study may implicate aberrant SF-1-mediated transcriptional regulation of SOX9 in 46,XY DSDs.

Original languageEnglish
Pages (from-to)1861-1874
Number of pages14
JournalHuman Mutation
Issue number12
Publication statusPublished - 1 Dec 2018


  • DSD
  • sex determination
  • SF-1
  • SOX9
  • testis-specific enhancer of SOX9

Cite this