OTX2 loss of function mutation causes anophthalmia and combined pituitary hormone deficiency with a small anterior and ectopic posterior pituitary.
BACKGROUND
Orthodenticle homeobox 2 (OTX2) is a transcription factor necessary for ocular and forebrain development. In humans, heterozygous mutations of OTX2 cause severe ocular malformations. However, whether mutations of OTX2 cause pituitary structural abnormalities or combined pituitary hormone deficiency (CPHD) has not been clarified.


OBJECTIVE
We surveyed the functional consequences of a novel OTX2 mutation that was detected in a patient with anophthalmia and CPHD.


METHODS
We examined a Japanese patient with growth disturbance, anophthalamia, and severe developmental delay. He showed deficiencies in GH, TSH, LH, FSH, and ACTH. Brain magnetic resonance imaging revealed a small anterior pituitary gland, invisible stalk, ectopic posterior lobe, and Chiari malformation.


RESULTS
Sequence analysis of OTX2 demonstrated a heterozygous two bases insertion [S136fsX178 (c.576-577insCT)] in exon 3. The mutant Otx2 protein localized to the nucleus, but did not activate the promoter of the HESX1 and POU1F1 gene, indicating a loss of function mutation. No dominant negative effect in the presence of wild-type Otx2 was observed.


CONCLUSIONS
This case indicates that the OTX2 mutation is a cause of CPHD. Further study of more patients with OTX2 defects is necessary to clarify the clinical phenotypes and endocrine defects caused by OTX2 mutations.
Department of Pediatrics, Hokkaido University School of Medicine, N15, W7, Sapporo, Japan 060-0835. tajeari@hokudai.med.ac.jp
Toshihiro
T
Tajima
Akira
A
Ohtake
Masaya
M
Hoshino
Shin
S
Amemiya
Nozomu
N
Sasaki
Katsura
K
Ishizu
Kenji
K
Fujieda
D000818:Animals; D000853:Anophthalmos / Q000235:genetics*; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D002828:Choristoma / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D051857:Otx Transcription Factors / Q000235:genetics*; D010903:Pituitary Gland, Anterior; D010904:Pituitary Gland, Posterior / Q000002:abnormalities*; D010907:Pituitary Hormones / Q000172:deficiency*
C497659:OTX2 protein, human; D051857:Otx Transcription Factors; D010907:Pituitary Hormones