title: XX males SRY negative: a confirmed cause of infertility.
abstract: BACKGROUND
  SOX9 is a widely expressed transcription factor playing several relevant functions during development and essential for testes differentiation. It is considered to be the direct target gene of the protein encoded by SRY and its overexpression in an XX murine gonad can lead to male development in the absence of Sry. Recently, a family was reported with a 178 kb duplication in the gene desert region ending about 500 kb upstream of SOX9 in which 46,XY duplicated persons were completely normal and fertile whereas the 46,XX ones were males who came to clinical attention because of infertility.
  
  
  RESULTS
  We report a family with two azoospermic brothers, both 46,XX, SRY negative, having a 96 kb triplication 500 kb upstream of SOX9. Both subjects have been analyzed trough oligonucleotide array-CGH and the triplication was confirmed and characterised through qPCR, defining the minimal region of amplification upstream of SOX9 associated with 46,XX infertile males, SRY negative.
  
  
  CONCLUSIONS
  Our results confirm that even in absence of SRY, complete male differentiation may occur, possibly driven by overexpression of SOX9 in the gonadal ridge, as a consequence of the amplification of a gene desert region. We hypothesize that this region contains gonadal specific long-range regulation elements whose alteration may impair the normal sex development. Our data show that normal XX males, with alteration in copy number or, possibly, in the critical sequence upstream to SOX9 are a new category of infertility inherited in a dominant way with expression limited to the XX background.
authors.affiliation: Medical Genetics, University of Pavia, via Forlanini 14, 27100 Pavia, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Vetro
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccone
authors.forename: Roberto
authors.initials: R
authors.lastname: Giorda
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Patricelli
authors.forename: Erika
authors.initials: E
authors.lastname: Della Mina
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
mesh_terms: D053713:Azoospermia / Q000235:genetics*; D002874:Chromosome Mapping; D055028:Comparative Genomic Hybridization; D005260:Female; D020440:Gene Duplication; D024282:Genes, sry; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D060888:Real-Time Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000235:genetics*; D012729:Sex Chromosome Aberrations; D025064:Sex Chromosome Disorders / Q000235:genetics*
chemical_list: D055758:SOX9 Transcription Factor