TY - JOUR
T1 - Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism
AU - Woods, Kathryn S.
AU - Cundall, Maria
AU - Turton, James
AU - Rizotti, Karine
AU - Mehta, Ameeta
AU - Palmer, Rodger
AU - Wong, Jacqueline
AU - Chong, W. K.
AU - Al-Zyoud, Mahmoud
AU - El-Ali, Maryam
AU - Otonkoski, Timo
AU - Martinez-Barbera, Juan Pedro
AU - Thomas, Paul Q.
AU - Robinson, Iain C.
AU - Lovell-Badge, Robin
AU - Woodward, Karen J.
AU - Dattani, Mehul T.
N1 - Funding Information:
We thank all the pediatricians and patients who participated in the study. This study was supported by grants from the Medical Research Council U.K. (to M.T.D., K.S.W., J.T., A.M., and M.C.), the Wellcome Trust (to K.J.W.), Novo Nordisk (to A.M.), and the Child Growth Foundation (to A.M.). Research at the Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust benefits from research-and-development funding received from the NHS Executive.
PY - 2005/5
Y1 - 2005/5
N2 - Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.
AB - Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.
UR - http://www.scopus.com/inward/record.url?scp=20244386714&partnerID=8YFLogxK
U2 - 10.1086/430134
DO - 10.1086/430134
M3 - Article
C2 - 15800844
AN - SCOPUS:20244386714
SN - 0002-9297
VL - 76
SP - 833
EP - 849
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -