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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
Author(s) -
Ushijima Kikumi,
Ogawa Yuya,
Terao Miho,
Asakura Yumi,
Muroya Koji,
Hayashi Mie,
Ishii Tomohiro,
Hasegawa Tomonobu,
Sekido Ryohei,
Fukami Maki,
Takada Shuji,
Narumi Satoshi
Publication year - 2021
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.62063
Subject(s) - sox9 , missense mutation , transactivation , testis determining factor , sex reversal , ovotestis , biology , phenotype , transcription factor , genetics , microbiology and biotechnology , gene , gonad , y chromosome , endocrinology
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 ( Sox9 E50K/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.