TY - JOUR
T1 - Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development
AU - Benko, Sabina
AU - Gordon, Christopher T.
AU - Mallet, Delphine
AU - Sreenivasan, Rajini
AU - Thauvin-Robinet, Christel
AU - Brendehaug, Atle
AU - Thomas, Sophie
AU - Bruland, Ove
AU - David, Michel
AU - Nicolino, Marc
AU - Labalme, Audrey
AU - Sanlaville, Damien
AU - Callier, Patrick
AU - Malan, Valerie
AU - Huet, Frédéric
AU - Molven, Anders
AU - Dijoud, Frédérique
AU - Munnich, Arnold
AU - Faivre, Laurence
AU - Amiel, Jeanne
AU - Harley, Vincent
AU - Houge, Gunnar
AU - Morel, Yves
AU - Lyonnet, Stanislas
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84856009018&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2011-100255
DO - 10.1136/jmedgenet-2011-100255
M3 - Article
C2 - 22051515
AN - SCOPUS:84856009018
SN - 0022-2593
VL - 48
SP - 825
EP - 830
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 12
ER -