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Mutant NR5A1/SF‐1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer
Author(s) -
Sreenivasan Rajini,
Ludbrook Louisa,
Fisher Brett,
Declosmenil Faustine,
Knower Kevin C.,
Croft Brittany,
Bird Anthony D.,
Ryan Janelle,
Bashamboo Anu,
Sinclair Andrew H.,
Koopman Peter,
McElreavey Ken,
Poulat Francis,
Harley Vincent R.
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23603
Subject(s) - steroidogenic factor 1 , biology , sox9 , disorders of sex development , enhancer , mutant , testis determining factor , mutation , sex reversal , genetics , in silico , nuclear receptor , gonadal dysgenesis , phenotype , zinc finger , transcription factor , microbiology and biotechnology , gene , endocrinology , y chromosome
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 T estis‐specific E nhancer of S ox9 co re 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.