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.401C>G (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.

journal_name

Eur J Endocrinol

authors

Gorbenko Del Blanco D,Romero CJ,Diaczok D,de Graaff LC,Radovick S,Hokken-Koelega AC

doi

10.1530/EJE-12-0333

subject

Has Abstract

pub_date

2012-09-01 00:00:00

pages

441-52

issue

3

eissn

0804-4643

issn

1479-683X

pii

EJE-12-0333

journal_volume

167

pub_type

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