A novel OTX2 mutation in a patient with combined pituitary hormone deficiency, pituitary malformation, and an underdeveloped left optic nerve

Abstract

Orthodenticle homolog 2 (OTX2) is a homeobox family transcription factor required for brain and eye formation. Various genetic alterations in OTX2 have been described, mostly in patients with severe ocular malformations. In order to expand the knowledge of the spectrum of OTX2 mutation, we performed OTX2 mutation screening in 92 patients with combined pituitary hormone deficiency (CPHD). We directly sequenced the coding regions and exon-intron boundaries of OTX2 in 92 CPHD patients from the Dutch HYPOPIT study in whom mutations in the classical CPHD genes PROP1, POU1F1, HESX1, LHX3, and LHX4 had been ruled out. Among 92 CPHD patients, we identified a novel heterozygous missense mutation c.401COG (p.Pro134Arg) in a patient with CPHD, pituitary malformation, and an underdeveloped left optic nerve. Binding of both the wild-type and mutant OTX2 proteins to bicoid binding sites was equivalent; however, the mutant OTX2 exhibited decreased transactivation. We describe a novel missense heterozygous OTX2 mutation that acts as a dominant negative inhibitor of target gene expression in a patient with CPHD, pituitary malformation, and optic nerve hypoplasia. We provide an overview of all OTX2 mutations described till date, which show that OTX2 is a promising candidate gene for genetic screening of patients with CPHD or isolated GH deficiency (IGHD). As the majority of the OTX2 mutations found in patients with CPHD, IGHD, or short stature have been found in exon 5, we recommend starting mutational screening in those patients in exon 5 of the gene.

A Novel Mutation in <b><i>OTX2</i></b> Causes Combined Pituitary Hormone Deficiency, Bilateral Microphthalmia, and Agenesis of the Left Internal Carotid Artery

“…CPHD, including ACTH deficiency, during the neonatal period is not a common finding in previous reports. To date, only two cases of ACTH deficiency during the neonatal period have been reported [8]. The possibility of transitory adrenal insufficiency in neonates should be considered since our diagnosis of ACTH deficiency was made based on random blood sampling in the neonatal period [9].…”

“…Agenesis or hypoplasia of the ICA is a rare vascular anomaly seen in about 0.01% of the population [10]. Twelve cases of agenesis of the ICA accompanied by CPHD have been reported so far [8,11,12,13,14,15,16,17,18,19,20,21]. To the best of our knowledge, this is the first time that a genetic mutation was identified in a patient with agenesis of the ICA and CPHD.…”

“…A luciferase reporter vector was constructed by inserting the HESX1 promoter sequence (-405 to +267 bp) into a pGL4.24 [luc2P/minP] vector (Promega, Madison, Wis., USA). A luciferase reporter using POU1F1 promoter had previously been described [8]. …”

Pituitary development: a complex, temporal regulated process dependent on specific transcriptional factors

“…Therefore, it is possible that in response to SHH signalling, GLI proteins activate other target genes directly involved in pituitary organogenesis (Franca et al 2010). Otx2 is another TF that is not expressed in the pituitary tissues themselves (Diaczok et al 2008, Gorbenko Del Blanco et al 2012. This TF encodes a bicoid protein that is important for eye and forebrain formation (Schilter et al 2011, Gorbenko Del Blanco et al 2012.…”

“…Otx2 is another TF that is not expressed in the pituitary tissues themselves (Diaczok et al 2008, Gorbenko Del Blanco et al 2012. This TF encodes a bicoid protein that is important for eye and forebrain formation (Schilter et al 2011, Gorbenko Del Blanco et al 2012. OTX2 is also responsible for Hesx1 expression regulation (Diaczok et al 2008).…”