Identification of the first promoter-specific gain-of-function SOX9 missense variant (p.E50K) in a patient with 46,XX ovotesticular disorder of sex development

Kikumi Ushijima, Yuya Ogawa, Miho Terao, Yumi Asakura, Koji Muroya, Mie Hayashi, Tomohiro Ishii, Tomonobu Hasegawa, Ryohei Sekido, Maki Fukami, Shuji Takada, Satoshi Narumi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


SOX9, a transcription factor, is expressed in the undifferentiated XX and XY gonads. SRY induces significant upregulation of SOX9 expression in XY gonads. Loss-of-function SOX9 variants cause testicular dysgenesis in 46,XY patients, while duplication of the total gene or the upstream regulatory region results in testicular development in 46,XX patients. However, gain-of-function (GoF) SOX9 variants have not been reported previously. We report the case of a 16-year-old female patient with a 46,XX karyotype who had masculinized external genitalia and unilateral ovotestis. Next-generation sequencing-based genetic screening for disorders of sex development led to the identification of a novel SOX9 variant (p.Glu50Lys), transmitted from the phenotypically normal father. Expression analysis showed that E50K-SOX9 enhanced transactivation of the luciferase reporter containing the testis enhancer sequence core element compared with that containing the wildtype-SOX9. This GoF activity was not observed in the luciferase reporter containing Amh, the gene for anti-Müllerian hormone. We genetically engineered female mice (Sox9E50K/E50K), and they showed no abnormalities in the external genitalia or ovaries. In conclusion, a novel SOX9 variant with a promoter-specific GoF activity was identified in vitro; however, the disease phenotype was not recapitulated by the mouse model. At present, the association between the GoF SOX9 variant and the ovotestis phenotype remains unclear. Future studies are needed to verify the possible association.

Original languageEnglish
Pages (from-to)1067-1075
Number of pages9
JournalAmerican Journal of Medical Genetics, Part A
Issue number4
Early online date5 Jan 2021
Publication statusPublished - 1 Apr 2021


  • disorders of sex development
  • promoter-specific gain-of-function variant
  • SOX9
  • testis enhancer sequence core element


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