Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype.
BACKGROUND
Although recent studies have suggested a positive role of OTX2 in pituitary as well as ocular development and function, detailed pituitary phenotypes in OTX2 mutations and OTX2 target genes for pituitary function other than HESX1 and POU1F1 remain to be determined.


OBJECTIVE
We aimed to examine such unresolved issues.


METHODS
We studied 94 Japanese patients with various ocular or pituitary abnormalities.


RESULTS
We identified heterozygous p.K74fsX103 in case 1, p.A72fsX86 in case 2, p.G188X in two unrelated cases (3 and 4), and a 2,860,561-bp microdeletion involving OTX2 in case 5. Clinical studies revealed isolated GH deficiency in cases 1 and 5; combined pituitary hormone deficiency in case 3; abnormal pituitary structures in cases 1, 3, and 5; and apparently normal pituitary function in cases 2 and 4, together with ocular anomalies in cases 1-5. The wild-type Orthodenticle homeobox 2 (OTX2) protein transactivated the GNRH1 promoter as well as the HESX1, POU1F1, and IRBP (interstitial retinoid-binding protein) promoters, whereas the p.K74fsX103-OTX2 and p.A72fsX86-OTX2 proteins had no transactivation functions and the p.G188X-OTX2 protein had reduced ( approximately 50%) transactivation functions for the four promoters, with no dominant-negative effect. cDNA screening identified positive OTX2 expression in the hypothalamus.


CONCLUSIONS
The results imply that OTX2 mutations are associated with variable pituitary phenotype, with no genotype-phenotype correlations, and that OTX2 can transactivate GNRH1 as well as HESX1 and POU1F1.
Dateki
Sumito
S
Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo 157-8535, Japan.
Kosaka
Kitaro
K
Hasegawa
Kosei
K
Tanaka
Hiroyuki
H
Azuma
Noriyuki
N
Yokoya
Susumu
S
Muroya
Koji
K
Adachi
Masanori
M
Tajima
Toshihiro
T
Motomura
Katsuaki
K
Kinoshita
Eiichi
E
Moriuchi
Hiroyuki
H
Sato
Naoko
N
Fukami
Maki
M
Ogata
Tsutomu
T
D000293:Adolescent; D000853:Anophthalmos / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008850:Microphthalmos / Q000235:genetics; D009154:Mutation; D051857:Otx Transcription Factors / Q000235:genetics*; D010641:Phenotype; D010900:Pituitary Diseases / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics
C489736:HESX1 protein, human; D018398:Homeodomain Proteins; C497659:OTX2 protein, human; D051857:Otx Transcription Factors; D011498:Protein Precursors; C050866:progonadoliberin I; D007987:Gonadotropin-Releasing Hormone