Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development

Sabina Benko, Christopher T. Gordon, Delphine Mallet, Rajini Sreenivasan, Christel Thauvin-Robinet, Atle Brendehaug, Sophie Thomas, Ove Bruland, Michel David, Marc Nicolino, Audrey Labalme, Damien Sanlaville, Patrick Callier, Valerie Malan, Frédéric Huet, Anders Molven, Frédérique Dijoud, Arnold Munnich, Laurence Faivre, Jeanne AmielVincent Harley, Gunnar Houge, Yves Morel, Stanislas Lyonnet

Research output: Contribution to journalArticleResearchpeer-review

158 Citations (Scopus)

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 noncoding 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.

Original languageEnglish
Pages (from-to)825-830
Number of pages6
JournalJournal of Medical Genetics
Volume48
Issue number12
DOIs
Publication statusPublished - Dec 2011
Externally publishedYes

Cite this