Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development

Gorjana Robevska, Jocelyn A van den Bergen, Thomas Ohnesorg, Stefanie Eggers, Chloe Hanna, Remko Hersmus, Elizabeth M Thompson, Anne Baxendale, Charles F Verge, Antony R Lafferty, Nanis S Marzuki, Ardy Santosa, Nurin A Listyasari, Stefan Riedl, Garry Warne, Leendert Looijenga, Sultana Faradz, Katie L Ayers, Andrew H Sinclair

Research output: Contribution to journalArticlepeer-review

Abstract

Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans-activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Müllerian development. There was little correlation between the severity of the phenotype and the nature of the NR5A1 variant. We report two familial cases of NR5A1 deficiency with evidence of variable expressivity; we also report on individuals with oligogenic inheritance. Finally, we found that the nature of the NR5A1 variant does not inform patient outcomes (including pubertal androgenization and malignancy risk). This study adds nine novel pathogenic NR5A1 variants to the pool of diagnostic variants. It highlights a greater need for understanding the complexity of SF1 function and the additional factors that contribute.

Original languageEnglish
Pages (from-to)124-139
Number of pages16
JournalHuman mutation
Volume39
Issue number1
DOIs
Publication statusPublished - Jan 2018
Externally publishedYes

Keywords

  • Alleles
  • Amino Acid Sequence
  • Disorder of Sex Development, 46,XY/diagnosis
  • Disorders of Sex Development/diagnosis
  • Female
  • Genetic Association Studies/methods
  • Genetic Variation
  • Genotype
  • Humans
  • Male
  • Models, Anatomic
  • Mutation
  • Phenotype
  • Protein Conformation
  • Protein Domains/genetics
  • RNA Splice Sites
  • Sequence Analysis, DNA
  • Steroidogenic Factor 1/chemistry

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