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A Novel Dominant Negative Mutation of OTX2 Associated with Combined Pituitary Hormone Deficiency

Division of Pediatric Endocrinology (D.D., C.R., S.R.), Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Medical Genetics (J.Z.), Indiana University School of Medicine-Northwest, Gary, Indiana 46408; and Division of Pediatric Endocrinology (I.M.), University of Medicine and Dentistry, New Jersey (UMDNJ)-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901

Address all correspondence and requests for reprints to: Sally Radovick, M.D., Division of Pediatric Endocrinology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 406, Baltimore, Maryland 21287. E-mail: sradovick{at}jhmi.edu.

Context: Combined pituitary hormone deficiency (CPHD) is characterized by deficiencies in more than one anterior pituitary hormone. Mutations in developmental factors responsible for pituitary cell specification and gene expression have been found in CPHD patients. OTX2, a bicoid class homeodomain protein, is necessary for both forebrain development and transactivation of the HESX1 promoter, but as of yet, has not been associated with CPHD.

Objective: The goal of this study was to identify and characterize novel mutations in pituitary specific transcription factors from CPHD patients.

Design: Genomic DNA was isolated from patients with hypopituitarism to amplify and sequence eight pituitary specific transcription factors (HESX1, LHX3, LHX4, OTX2, PITX2, POU1F1, PROP1, and SIX6). Characterization of novel mutations is based on structural and functional studies.

Results: We describe two unrelated children with CPHD who presented with neonatal hypoglycemia, and deficiencies of GH, TSH, LH, FSH, and ACTH. Magnetic resonance imaging revealed anterior pituitary hypoplasia with an ectopic posterior pituitary. A novel heterozygous OTX2 mutation (N233S) was identified. Wild-type and mutant OTX2 proteins bind equivalently to bicoid binding sites, whereas mutant OTX2 revealed decreased transactivation.

Conclusions: A novel mutation in OTX2 binds normally to target genes and acts as a dominant negative inhibitor of HESX1 gene expression. This suggests that the expression of HESX1, required for spaciotemporal development of anterior pituitary cell types, when disrupted, results in an absent or underdeveloped anterior pituitary with diminished hormonal expression. These results demonstrate a novel mechanism for CPHD and extend our knowledge of the spectrum of gene mutations causing CPHD.

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				R. Larder and P. L. Mellon Otx2 Induction of the Gonadotropin-releasing Hormone Promoter Is Modulated by Direct Interactions with Grg Co-repressors J. Biol. Chem., June 19, 2009; 284(25): 16966 - 16978. [Abstract] [Full Text] [PDF]