OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters.

Abstract

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 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: Sumito Dateki, Maki Fukami, Naoko Sato, Kouji Muroya, Masanori Adachi, Tsutomu Ogata
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 93 Issue 10 Pg. 3697-702 (Oct 2008) ISSN: 0021-972X [Print] United States
• PMID: 18628516 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Eye Proteins
• HESX1 protein, human
• Homeodomain Proteins
• OTX2 protein, human
• Otx Transcription Factors
• POU1F1 protein, human
• Retinol-Binding Proteins
• Transcription Factor Pit-1
• interstitial retinol-binding protein
• Human Growth Hormone

Topics

• Anophthalmos (complications, genetics)
• Child
• DNA Mutational Analysis
• Eye Proteins (genetics)
• Female
• Follow-Up Studies
• Growth Disorders (complications, genetics)
• Homeodomain Proteins (genetics)
• Human Growth Hormone (deficiency)
• Humans
• Otx Transcription Factors (genetics, metabolism, physiology)
• Point Mutation (physiology)
• Promoter Regions, Genetic
• Retinol-Binding Proteins (genetics)
• Tissue Distribution
• Transcription Factor Pit-1 (genetics)
• Transgenes (physiology)