title: Interchromosomal insertional translocation at Xq26.3 alters SOX3 expression in an individual with XX male sex reversal.
abstract: BACKGROUND
  46,XX male sex reversal occurs in approximately 1: 20 000 live births and is most commonly caused by interchromosomal translocations of the Y-linked sex-determining gene, SRY. Rearrangements of the closely related SOX3 gene on the X chromosome are also associated with 46,XX male sex reversal. It has been hypothesized that sex reversal in the latter is caused by ectopic expression of SOX3 in the developing urogenital ridge where it triggers male development by acting as an analog of SRY. However, altered regulation of SOX3 in individuals with XX male sex reversal has not been demonstrated.
  
  
  METHODS
  Here we report a boy with SRY-negative XX male sex reversal who was diagnosed at birth with a small phallus, mixed gonads, and borderline-normal T. Molecular characterization of the affected individual was performed using array comparative genomic hybridization, fluorescent in situ hybridization of metaphase chromosomes, whole-genome sequencing, and RT-PCR expression analysis of lymphoblast cell lines.
  
  
  RESULTS
  The affected male carries ∼774-kb insertion translocation from chromosome 1 into a human-specific palindromic sequence 82 kb distal to SOX3. Importantly, robust SOX3 expression was identified in cells derived from the affected individual but not from control XX or XY cells, indicating that the translocation has a direct effect on SOX3 regulation.
  
  
  CONCLUSIONS
  This is the first demonstration of altered SOX3 expression in an individual with XX male sex reversal and suggests that SOX3 can substitute for SRY to initiate male development in humans.
authors.affiliation: School of Molecular & Biomedical Science (B.H., J.H., P.T.), Robinson Research Institute (B.H., J.H., M.C., M.S., J.G., P.T.), School of Pediatrics and Reproductive Health (M.C., M.S., J.G.), The University of Adelaide, Adelaide, Australia 5005; Manchester Centre For Genomic Medicine (J.I., J.C.-S.), Central Manchester National Health Service Foundation Trust, University of Manchester, Manchester M13 9WL; and Department of Child Health (L.P.), Royal Manchester Children's Hospital, University of Manchester, Manchester M13 9WL.
authors.forename: Bryan
authors.initials: B
authors.lastname: Haines
authors.forename: James
authors.initials: J
authors.lastname: Hughes
authors.forename: Mark
authors.initials: M
authors.lastname: Corbett
authors.forename: Marie
authors.initials: M
authors.lastname: Shaw
authors.forename: Josie
authors.initials: J
authors.lastname: Innes
authors.forename: Leena
authors.initials: L
authors.lastname: Patel
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.forename: Paul
authors.initials: P
authors.lastname: Thomas
mesh_terms: D058531:46, XX Testicular Disorders of Sex Development / Q000235:genetics*; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008297:Male; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D012729:Sex Chromosome Aberrations; D014178:Translocation, Genetic
chemical_list: C527785:SOX3 protein, human; D055748:SOXB1 Transcription Factors