Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype

Sumito Dateki, Kitaro Kosaka, Kousei Hasegawa, Hiroyuki Tanaka, Noriyuki Azuma, Susumu Yokoya, Koji Muroya, Masanori Adachi, Toshihiro Tajima, Katsuaki Motomura, Eiichi Kinoshita, Hiroyuki Moriuchi, Naoko Sato, Maki Fukami, Tsutomu Ogata

Research output: Contribution to journalArticle

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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 (∼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.

Original languageEnglish
Pages (from-to)756-764
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume95
Issue number2
DOIs
Publication statusPublished - Feb 2010

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Homeobox Genes
Phenotype
Mutation
Homeodomain Proteins
Retinol-Binding Proteins
Proteins
Pituitary Hormones
Transcriptional Activation
Pituitary Dwarfism
Screening
Complementary DNA
Genes
Genetic Association Studies
Hypothalamus

ASJC Scopus subject areas

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

Cite this

Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype. / Dateki, Sumito; Kosaka, Kitaro; Hasegawa, Kousei; Tanaka, Hiroyuki; Azuma, Noriyuki; Yokoya, Susumu; Muroya, Koji; Adachi, Masanori; Tajima, Toshihiro; Motomura, Katsuaki; Kinoshita, Eiichi; Moriuchi, Hiroyuki; Sato, Naoko; Fukami, Maki; Ogata, Tsutomu.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 95, No. 2, 02.2010, p. 756-764.

Research output: Contribution to journalArticle

Dateki, S, Kosaka, K, Hasegawa, K, Tanaka, H, Azuma, N, Yokoya, S, Muroya, K, Adachi, M, Tajima, T, Motomura, K, Kinoshita, E, Moriuchi, H, Sato, N, Fukami, M & Ogata, T 2010, 'Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype', Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 2, pp. 756-764. https://doi.org/10.1210/jc.2009-1334
Dateki, Sumito ; Kosaka, Kitaro ; Hasegawa, Kousei ; Tanaka, Hiroyuki ; Azuma, Noriyuki ; Yokoya, Susumu ; Muroya, Koji ; Adachi, Masanori ; Tajima, Toshihiro ; Motomura, Katsuaki ; Kinoshita, Eiichi ; Moriuchi, Hiroyuki ; Sato, Naoko ; Fukami, Maki ; Ogata, Tsutomu. / Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype. In: Journal of Clinical Endocrinology and Metabolism. 2010 ; Vol. 95, No. 2. pp. 756-764.
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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 (∼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.",
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T1 - Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype

AU - Dateki, Sumito

AU - Kosaka, Kitaro

AU - Hasegawa, Kousei

AU - Tanaka, Hiroyuki

AU - Azuma, Noriyuki

AU - Yokoya, Susumu

AU - Muroya, Koji

AU - Adachi, Masanori

AU - Tajima, Toshihiro

AU - Motomura, Katsuaki

AU - Kinoshita, Eiichi

AU - Moriuchi, Hiroyuki

AU - Sato, Naoko

AU - Fukami, Maki

AU - Ogata, Tsutomu

PY - 2010/2

Y1 - 2010/2

N2 - 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 (∼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.

AB - 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 (∼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.

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