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: 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/L after insulin and arginine stimulations, respectively; serum IGF-1: 37 ng/mL) at 3 9/12 years 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 wildtype and the 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 wildtype 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.