title: Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.
abstract: BACKGROUND
  The early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off.
  
  
  RESULTS
  Through copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517-595 kb upstream of the SOX9 promoter.
  
  
  CONCLUSIONS
  These data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.
authors: INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.
authors: Sabina
authors: S
authors: Benko
authors: Christopher T
authors: CT
authors: Gordon
authors: Delphine
authors: D
authors: Mallet
authors: Rajini
authors: R
authors: Sreenivasan
authors: Christel
authors: C
authors: Thauvin-Robinet
authors: Atle
authors: A
authors: Brendehaug
authors: Sophie
authors: S
authors: Thomas
authors: Ove
authors: O
authors: Bruland
authors: Michel
authors: M
authors: David
authors: Marc
authors: M
authors: Nicolino
authors: Audrey
authors: A
authors: Labalme
authors: Damien
authors: D
authors: Sanlaville
authors: Patrick
authors: P
authors: Callier
authors: Valerie
authors: V
authors: Malan
authors: Frédéric
authors: F
authors: Huet
authors: Anders
authors: A
authors: Molven
authors: Frédérique
authors: F
authors: Dijoud
authors: Arnold
authors: A
authors: Munnich
authors: Laurence
authors: L
authors: Faivre
authors: Jeanne
authors: J
authors: Amiel
authors: Vincent
authors: V
authors: Harley
authors: Gunnar
authors: G
authors: Houge
authors: Yves
authors: Y
authors: Morel
authors: Stanislas
authors: S
authors: Lyonnet
mesh_terms: D058489:46, XX Disorders of Sex Development / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000483:Alleles; D002648:Child; D002874:Chromosome Mapping; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D020440:Gene Duplication; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018238:Gonadoblastoma / Q000235:genetics* / Q000473:pathology; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D010375:Pedigree; D012045:Regulatory Sequences, Nucleic Acid; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051876:Sex-Determining Region Y Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein