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

다국어 초록 (Multilingual Abstract)

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.
Steroidogenic Factor 1 mutations cause 46,XY disorders of sex development (DSD). Patient DNA was sequenced and mutant SF‐1 proteins examined for transcriptional activity, protein expression, sub‐cellular localization and in silico structural defects. Fifteen of the 20 mutants reduce SF‐1 activation of a SOX9 enhancer, 11 with atypical sub‐cellular localization. Fourteen SF‐1 mutants were predicted to alter DNA, ligand or cofactor interactions. Our study implicates aberrant SF‐1 mediated transcriptional regulation of SOX9 in 46,XY DSD.