A Novel Dominant Negative Mutation of OTX2 Associated with Combined Pituitary Hormone Deficiency

Diaczok, Daniel; Romero, Christopher J.; Zunich, Janice; Marshall, Ian; Radovick, Sally

doi:10.1210/jc.2008-1189

Cited by 121 publications

(100 citation statements)

References 45 publications

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“…An ectopic or undescended posterior pituitary lobe is also a frequent finding in patients with GH deficiency, especially CPHD. Its presence on MRI has been increasingly used for the diagnosis of (Diaczok et al 2008, Dateki et al 2010. In addition, mutations in these early acting factors may present as part of a syndrome in patients that manifest abnormalities in extra-pituitary structures that share a common embryological origin with the pituitary gland, such as the eye and forebrain.…”

Section: Human Mutationsmentioning

confidence: 99%

Role of GLI2 in hypopituitarism phenotype

Arnhold¹,

França²,

Carvalho³

et al. 2015

Journal of Molecular Endocrinology

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GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was R0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.

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Section: Human Mutationsmentioning

confidence: 99%

Role of GLI2 in hypopituitarism phenotype

Arnhold¹,

França²,

Carvalho³

et al. 2015

Journal of Molecular Endocrinology

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“…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.…”

Section: Early Organogenesis: Rathke's Pouch Invaginationmentioning

confidence: 99%

“…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). Hesx1 is the first pituitary-specific TF to be expressed at or before E6 .…”

Section: Early Organogenesis: Rathke's Pouch Invaginationmentioning

confidence: 99%

“…Hesx1 expression begins in the rostral region and progresses dorsally; the restricted expression of this TF is responsible for Rathke's pouch formation (Hermesz et al 1996). HESX1 is important for midline formation and regulates the expression of other TFs (Hermesz et al 1996, Diaczok et al 2008, Reynaud et al 2011; Fig. 1).…”

Section: Early Organogenesis: Rathke's Pouch Invaginationmentioning

confidence: 99%

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

Moraes¹,

Vaisman²,

Conceição³

et al. 2012

Journal of Endocrinology

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Pituitary organogenesis is a highly complex and tightly regulated process that depends on several transcription factors (TFs), such as PROP1, PIT1 (POU1F1), HESX1, LHX3 and LHX4. Normal pituitary development requires the temporally and spatially organised expression of TFs and interactions between different TFs, DNA and TF co-activators. Mutations in these genes result in different combinations of hypopituitarism that can be associated with structural alterations of the central nervous system, causing the congenital form of panhypopituitarism. This review aims to elucidate the complex process of pituitary organogenesis, to clarify the role of the major TFs, and to compile the lessons learned from functional studies of TF mutations in panhypopituitarism patients and TF deletions or mutations in transgenic animals.

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“…The Sine oculis homeobox homolog (Six) gene family encodes a group of transcription factors that is related to homeobox-containing gene product in vertebrates by two conserved domains (Conte et al, 2005;Diaczok et al, 2008;Weasner and Kumar, 2009). Previous studies have reported that the Six family plays an important role in the entire development of the fly's visual system (Cheyette et al, 1994;Jean et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

A novel genetic variant of the goat Six6 gene and its association with production traits in Chinese goat breeds

Pan

Lan²,

Zhao³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. We looked for novel genetic variations within the Six6 gene by PCR-SSCP, DNA sequencing and forced RFLP-PCR and estimated their associations with production traits in 2132 goats of eight indigenous Chinese breeds. A novel single nucleotide polymorphism (NM_001104993.1: g.232T>C) within the goat Six6 gene was identified. The frequencies of allele "C" varied from 0.8621 to 1.000, which were in Hardy-Weinberg equilibrium. Genotype and allele frequencies were found to be significantly different in the breeds. Association analysis revealed a significant relationship between genotypes and cannon circumference in Hainan black goats (P = 0.047); adult individuals with genotype CT showed higher cannon circumference than those with genotype CC. Another significant association of genotypes with fiveyear-old fiber length was found in Inner Mongolia white cashmere goats (P = 0.002). In addition, individuals with genotype CT had longer fiber length than those with genotype CC. The data revealed that the Six6 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 10 (4): 3888-3900 (2011) A novel genetic variant of the goat Six6 gene 3889 gene positively affects growth traits and cashmere traits. Polymorphism of Six6-PstI could be useful as a DNA marker for goat breeding and genetics via marker-assisted selection.

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A Novel Dominant Negative Mutation of OTX2 Associated with Combined Pituitary Hormone Deficiency

Cited by 121 publications

References 45 publications

Role of GLI2 in hypopituitarism phenotype

Role of GLI2 in hypopituitarism phenotype

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

A novel genetic variant of the goat Six6 gene and its association with production traits in Chinese goat breeds

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