title: Testicular differentiation factor SF-1 is required for human spleen development.
abstract: The transcription factor steroidogenic factor 1 (SF-1; also known as NR5A1) is a crucial mediator of both steroidogenic and nonsteroidogenic tissue differentiation. Mutations within SF1 underlie different disorders of sexual development (DSD), including sex reversal, spermatogenic failure, ovarian insufficiency, and adrenocortical deficiency. Here, we identified a recessive mutation within SF1 that resulted in a substitution of arginine to glutamine at codon 103 (R103Q) in a child with both severe 46,XY-DSD and asplenia. The R103Q mutation decreased SF-1 transactivation of TLX1, a transcription factor that has been shown to be essential for murine spleen development. Additionally, the SF1 R103Q mutation impaired activation of steroidogenic genes, without affecting synergistic SF-1 and sex-determining region Y (SRY) coactivation of the testis development gene SOX9. Together, our data provide evidence that SF-1 is required for spleen development in humans via transactivation of TLX1 and that mutations that only impair steroidogenesis, without altering the SF1/SRY transactivation of SOX9, can lead to 46,XY-DSD.
authors.forename: David
authors.initials: D
authors.lastname: Zangen
authors.forename: Yotam
authors.initials: Y
authors.lastname: Kaufman
authors.forename: Ehud
authors.initials: E
authors.lastname: Banne
authors.forename: Ariella
authors.initials: A
authors.lastname: Weinberg-Shukron
authors.forename: Abdulsalam
authors.initials: A
authors.lastname: Abulibdeh
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Garfinkel
authors.forename: Dima
authors.initials: D
authors.lastname: Dweik
authors.forename: Moein
authors.initials: M
authors.lastname: Kanaan
authors.forename: Núria
authors.initials: N
authors.lastname: Camats
authors.forename: Christa
authors.initials: C
authors.lastname: Flück
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D003062:Codon / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D059446:Heterotaxy Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051876:Sex-Determining Region Y Protein / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000254:growth & development* / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D003062:Codon; D018398:Homeodomain Proteins; C515057:NR5A1 protein, human; D011518:Proto-Oncogene Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; D054339:Steroidogenic Factor 1; C071250:TLX1 protein, human