Abstract:

CONTEXT: 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.
SUBJECTS: 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.

日本語要旨:

全国から集積した下垂体機能異常症患者94例のゲノムDNAを対象として遺伝子解析を行い、５例でOTX2遺伝子異常を同定した。さらに、OTX2変異に起因する下垂体機能低下症の病像を明確にした。また、細胞実験からOTX2が下垂体ホルモン調節に関与する機序を明らかとした。