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Enhanced Repression by HESX1 as a Cause of Hypopituitarism and Septooptic Dysplasia

Section of Endocrinology (R.N.C., C.Y., A.S., M.J.), Department of Medicine, University of Chicago, Chicago, Illinois 60637; Division of Endocrinology (L.E.C., D.B.), Department of Medicine, Children’s Hospital, Boston, Massachusetts 02115; and Section of Pediatric Endocrinology (C.Y., S.R.), Department of Pediatrics, University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Ronald Cohen, M.D., Section of Endocrinology, Department of Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637. E-mail: roncohen{at}medicine.bsd.uchicago.edu.

HESX1 is a paired-like homeodomain transcription factor that functions as a repressor of PROP1-mediated gene stimulation. Mutations in HESX1 have been implicated in cases of septooptic dysplasia and congenital hypopituitarism. All mutations in HESX1 identified to date have resulted in impaired DNA binding and defective HESX1 action. We have identified a novel HESX1 mutation in genomic nucleotide position 1684 (g.1684delG), which results in a mutant protein with increased DNA binding. In turn, this mutation causes increased repression of PROP1-dependent gene activity. These data suggest that enhancement of transcriptional repression during pituitary organogenesis is a novel mechanism for the development of congenital pituitary disorders.

This work was supported by grants from the National Institutes of Health (to R.N.C., L.E.C., and S.R.) and the Genentech Foundation for Growth and Development (to L.E.C.). M.J. was the recipient of a Howard Hughes Medical Institute Summer Student Research Fellowship.

Abbreviations: CMV, Cytomegalovirus; E13, embryonic d 13; NCoR, nuclear corepressor; PRL, prolactin; SOD, septooptic dysplasia; UAS, upstream activating sequence.

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