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OTX2 Mutation in a Patient with Anophthalmia, Short Stature, and Partial Growth Hormone Deficiency: Functional Studies Using the IRBP, HESX1, and POU1F1 Promoters

Department of Endocrinology and Metabolism (S.D., M.F., N.S., T.O.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (S.D.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501; and Division of Endocrinology and Metabolism (K.M., M.A.), Kanagawa Children’s Medical Center, Yokohama 232-8555, Japan

Address all correspondence and requests for reprints to: Dr. T. Ogata, Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo 157-8535, Japan. E-mail: tomogata{at}nch.go.jp.

Context: OTX2 is a transcription factor gene essential for eye development. Although recent studies suggest the involvement of OTX2 in pituitary function, there is no report demonstrating a positive role of OTX2 in the pituitary function.

Objective: The objective of the study was to report the results of functional studies indicating the relevance of OTX2 to pituitary function.

Patient: A Japanese female patient with bilateral anophthalmia was found to have short stature (height, –3.3 SD) and isolated partial GH deficiency (peak serum GH 3.1 and 9.7 µg/liter after insulin and arginine stimulations, respectively; serum IGF-I 37 ng/ml) at 3 yr 9 months of age. Magnetic resonance imaging delineated apparently normal pituitary gland.

Results: Mutation analysis showed a de novo heterozygous frameshift mutation (c.402insC) that is predicted to retain the homeodomain but lose the transactivation domain. Functional studies revealed that the wild-type and mutant OTX2 proteins localized to the nucleus and bound to the target sequences within the IRBP (interstitial retinoid-binding protein), HESX1 (HESX homeobox 1), and POU1F1 promoters. Furthermore, the wild-type OTX2 protein markedly transactivated the promoters of IRBP (27-fold), HESX1 (4.5-fold), and POU1F1 (19-fold), whereas the mutant OTX2 protein barely retained the transactivation activities and had no dominant-negative effects.

Conclusions: The results provide direct evidence for OTX2 being involved in the pituitary function. It is likely that the heterozygous severe OTX2 loss-of-function mutation caused GH deficiency and short stature, primarily because of decreased transactivation function for HESX1 and POU1F1.