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

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1861-1874
Number of pages14
JournalHuman Mutation
Volume39
Issue number12
DOIs
Publication statusPublished - 1 Dec 2018

Keywords

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

Cite this

Sreenivasan, R., Ludbrook, L. M., Fisher, B. D., Declosmenil, F., Knower, K. C., Croft, B. M., ... Harley, V. R. (2018). Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer. Human Mutation, 39(12), 1861-1874. https://doi.org/10.1002/humu.23603
Sreenivasan, Rajini ; Ludbrook, Louisa Mabel ; Fisher, Brett Daniel ; Declosmenil, Faustine ; Knower, Kevin C. ; Croft, Brittany Marie ; Bird, Anthony Daniel ; Ryan, Janelle ; Bashamboo, Anu ; Sinclair, Andrew ; Koopman, Peter ; McElreavey, Ken ; Poulat, Francis ; Harley, Vincent Russel. / Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer. In: Human Mutation. 2018 ; Vol. 39, No. 12. pp. 1861-1874.
@article{6fc4378bfce64ea594802ed013de701f,
title = "Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer",
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.",
keywords = "DSD, sex determination, SF-1, SOX9, testis-specific enhancer of SOX9",
author = "Rajini Sreenivasan and Ludbrook, {Louisa Mabel} and Fisher, {Brett Daniel} and Faustine Declosmenil and Knower, {Kevin C.} and Croft, {Brittany Marie} and Bird, {Anthony Daniel} and Janelle Ryan and Anu Bashamboo and Andrew Sinclair and Peter Koopman and Ken McElreavey and Francis Poulat and Harley, {Vincent Russel}",
year = "2018",
month = "12",
day = "1",
doi = "10.1002/humu.23603",
language = "English",
volume = "39",
pages = "1861--1874",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Blackwell",
number = "12",

}

Sreenivasan, R, Ludbrook, LM, Fisher, BD, Declosmenil, F, Knower, KC, Croft, BM, Bird, AD, Ryan, J, Bashamboo, A, Sinclair, A, Koopman, P, McElreavey, K, Poulat, F & Harley, VR 2018, 'Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer', Human Mutation, vol. 39, no. 12, pp. 1861-1874. https://doi.org/10.1002/humu.23603

Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer. / Sreenivasan, Rajini; Ludbrook, Louisa Mabel; Fisher, Brett Daniel; Declosmenil, Faustine ; Knower, Kevin C.; Croft, Brittany Marie; Bird, Anthony Daniel; Ryan, Janelle; Bashamboo, Anu ; Sinclair, Andrew; Koopman, Peter; McElreavey, Ken ; Poulat, Francis; Harley, Vincent Russel.

In: Human Mutation, Vol. 39, No. 12, 01.12.2018, p. 1861-1874.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer

AU - Sreenivasan, Rajini

AU - Ludbrook, Louisa Mabel

AU - Fisher, Brett Daniel

AU - Declosmenil, Faustine

AU - Knower, Kevin C.

AU - Croft, Brittany Marie

AU - Bird, Anthony Daniel

AU - Ryan, Janelle

AU - Bashamboo, Anu

AU - Sinclair, Andrew

AU - Koopman, Peter

AU - McElreavey, Ken

AU - Poulat, Francis

AU - Harley, Vincent Russel

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

KW - DSD

KW - sex determination

KW - SF-1

KW - SOX9

KW - testis-specific enhancer of SOX9

UR - http://www.scopus.com/inward/record.url?scp=85052445073&partnerID=8YFLogxK

U2 - 10.1002/humu.23603

DO - 10.1002/humu.23603

M3 - Article

VL - 39

SP - 1861

EP - 1874

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 12

ER -

Sreenivasan R, Ludbrook LM, Fisher BD, Declosmenil F, Knower KC, Croft BM et al. Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer. Human Mutation. 2018 Dec 1;39(12):1861-1874. https://doi.org/10.1002/humu.23603