title: OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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 mug/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 ( approximately 27-fold), HESX1 ( approximately 4.5-fold), and POU1F1 ( approximately 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.
authors.affiliation: Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Sumito
authors.initials: S
authors.lastname: Dateki
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.forename: Naoko
authors.initials: N
authors.lastname: Sato
authors.forename: Kouji
authors.initials: K
authors.lastname: Muroya
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D000853:Anophthalmos / Q000150:complications / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006130:Growth Disorders / Q000150:complications / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D019382:Human Growth Hormone / Q000172:deficiency*; D006801:Humans; D051857:Otx Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017354:Point Mutation / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012177:Retinol-Binding Proteins / Q000235:genetics; D014018:Tissue Distribution; D050817:Transcription Factor Pit-1 / Q000235:genetics; D019076:Transgenes / Q000502:physiology; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D019382:Human Growth Hormone; D051857:Otx Transcription Factors; D012177:Retinol-Binding Proteins; D050817:Transcription Factor Pit-1; D000099214:Retinol-Binding Proteins, Interstitial; C489736:HESX1 protein, human; C497659:OTX2 protein, human; C494187:POU1F1 protein, human