A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency

Daniel Diaczok, Christopher Romero, Janice Zunich, Ian Marshall, Sally Radovick

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Context: Combined pituitary hormone deficiency (CPHD) is characterized by deficiencies in more than one anterior pituitary hormone. Mutations in developmental factors responsible for pituitary cell specification and gene expression have been found in CPHD patients. OTX2, a bicoid class homeodomain protein, is necessary for both forebrain development and transactivation of the HESX1 promoter, but as of yet, has not been associated with CPHD. Objective: The goal of this study was to identify and characterize novel mutations in pituitary specific transcription factors from CPHD patients. Design: Genomic DNA was isolated from patients with hypopituitarism to amplify and sequence eight pituitary specific transcription factors (HESX1, LHX3, LHX4, OTX2, PITX2, POU1F1, PROP1, and SIX6). Characterization of novel mutations is based on structural and functional studies. Results: We describe two unrelated children with CPHD who presented with neonatal hypoglycemia, and deficiencies of GH, TSH, LH, FSH, and ACTH. Magnetic resonance imaging revealed anterior pituitary hypoplasia with an ectopic posterior pituitary. A novel heterozygous OTX2 mutation (N233S) was identified. Wild-type and mutant OTX2 proteins bind equivalently to bicoid binding sites, whereas mutant OTX2 revealed decreased transactivation. Conclusions: A novel mutation in OTX2 binds normally to target genes and acts as a dominant negative inhibitor of HESX1 gene expression. This suggests that the expression of HESX1, required for spaciotemporal development of anterior pituitary cell types, when disrupted, results in an absent or under developed anterior pituitary with diminished hormonal expression. These results demonstrate a novel mechanism for CPHD and extend our knowledge of the spectrum of gene mutations causing CPHD.

Original languageEnglish
Pages (from-to)4351-4359
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number11
DOIs
StatePublished - Nov 2008

Fingerprint

Pituitary Hormones
Mutation
Gene expression
Transcriptional Activation
Transcription Factors
Genes
Anterior Pituitary Hormones
Homeodomain Proteins
Gene Expression
Hypopituitarism
Mutant Proteins
Prosencephalon
Hypothyroidism
Combined Pituitary Hormone Deficiency
Hypoglycemia
Adrenocorticotropic Hormone
Magnetic resonance imaging
Binding Sites
Magnetic Resonance Imaging
Specifications

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. / Diaczok, Daniel; Romero, Christopher; Zunich, Janice; Marshall, Ian; Radovick, Sally.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 93, No. 11, 11.2008, p. 4351-4359.

Research output: Contribution to journalArticle

Diaczok, Daniel ; Romero, Christopher ; Zunich, Janice ; Marshall, Ian ; Radovick, Sally. / A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. In: Journal of Clinical Endocrinology and Metabolism. 2008 ; Vol. 93, No. 11. pp. 4351-4359.
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AB - Context: Combined pituitary hormone deficiency (CPHD) is characterized by deficiencies in more than one anterior pituitary hormone. Mutations in developmental factors responsible for pituitary cell specification and gene expression have been found in CPHD patients. OTX2, a bicoid class homeodomain protein, is necessary for both forebrain development and transactivation of the HESX1 promoter, but as of yet, has not been associated with CPHD. Objective: The goal of this study was to identify and characterize novel mutations in pituitary specific transcription factors from CPHD patients. Design: Genomic DNA was isolated from patients with hypopituitarism to amplify and sequence eight pituitary specific transcription factors (HESX1, LHX3, LHX4, OTX2, PITX2, POU1F1, PROP1, and SIX6). Characterization of novel mutations is based on structural and functional studies. Results: We describe two unrelated children with CPHD who presented with neonatal hypoglycemia, and deficiencies of GH, TSH, LH, FSH, and ACTH. Magnetic resonance imaging revealed anterior pituitary hypoplasia with an ectopic posterior pituitary. A novel heterozygous OTX2 mutation (N233S) was identified. Wild-type and mutant OTX2 proteins bind equivalently to bicoid binding sites, whereas mutant OTX2 revealed decreased transactivation. Conclusions: A novel mutation in OTX2 binds normally to target genes and acts as a dominant negative inhibitor of HESX1 gene expression. This suggests that the expression of HESX1, required for spaciotemporal development of anterior pituitary cell types, when disrupted, results in an absent or under developed anterior pituitary with diminished hormonal expression. These results demonstrate a novel mechanism for CPHD and extend our knowledge of the spectrum of gene mutations causing CPHD.

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