Heterozygous Orthodenticle Homeobox 2 Mutations Are Associated with Variable Pituitary Phenotype

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

doi:10.1210/mend.24.1.9999

Cited by 21 publications

(37 citation statements)

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“…FOXC1 alterations (mutations or 6p25.3 deletions/ duplications) are involved in Axenfeld-Rieger anomaly or syndrome (MIM 601090, 602482, and 601631) and were recently shown to cause cerebellar vermis hypoplasia and to contribute to the Dandy-Walker continuum. 14 OTX2 deletions and heterozygous mutations cause syndromal micro-anophthalmia (MIM 600037 and 610125) 15 and developmental anomalies of the pituitary gland, 16 and OTX2 mutations can cause septo-optic dysplasia. 17 Family C and several previously described families were reported with OTX2 alterations in patients presenting micro-anophthalmia and/or pituitary deficiency but inherited from an asymptomatic parent, 9,16,18,19 suggesting the incomplete penetrance of OTX2-associated phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies

et al. 2012

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In 65 patients, who had unexplained ocular developmental anomalies (ODAs) with at least one other birth defect and/or intellectual disability, we performed oligonucleotide comparative genome hybridisation-based microarray analysis (array-CGH; 105A or 180K, Agilent Technologies). In four patients, array-CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development (FOXC1 or OTX2). In four other patients, we found three pathogenic deletions not classically associated with abnormal ocular morphogenesis, namely, del(17)(p13.3p13.3), del(10)(p14p15.3), and del(16)(p11.2p11.2). We also detected copy number variations of uncertain pathogenicity in two other patients. Rearranged segments ranged in size from 0.04 to 5.68 Mb. These results show that array-CGH provides a high diagnostic yield (15%) in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions. In addition to their importance for diagnosis and genetic counselling, these data may help identify genes involved in ocular development.

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Section: Discussionmentioning

confidence: 99%

Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies

et al. 2012

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“…In addition, 3 whole-gene deletions have been described (Ragge et al 2005;Henderson et al 2007Henderson et al , 2009Diaczok et al 2008;Dateki et al 2008Dateki et al , 2010Wyatt et al 2008;Tajima et al 2009). The first OTX2 mutations were reported in patients with severe ocular phenotypes and central nervous system abnormalities, such as seizures, short stature, and developmental delay (Ragge et al 2005).…”

Section: Introductionmentioning

confidence: 99%

“…OTX2 mutations are associated with variable pituitary phenotypes, with no genotype-phenotype correlation (Dateki et al 2010). In most cases, premature protein termination was predicted, either via a nonsense mutation creating a stop codon (p.Q99X, p.Y179X, (Ragge et al 2005); p.Q97X, p.Y31X, (Wyatt et al 2008); p.S318X, (Henderson et al 2009); p.G188X, (Dateki et al 2010) or a frameshift (c.81delC, c.117delCC, c.464insGC, (Ragge et al 2005; c.106dupC, c.371_372 delAG, (Wyatt et al 2008); c.402_403insC, (Dateki et al 2008); c.405_406insCT, (Tajima et al 2009);c.214_217delGCACinsCA, c.221_ 236del16, (Dateki et al 2010)), leading to a truncated mRNA that was destined for degradation by the nonsense mediated RNA decay (c.93C[G; C.106dupC; c.252delC) or expected to be inactive due to loss of the transactivation domain. Indeed, functional analysis revealed these OTX2 mutations to be loss-of-function mutations (Chatelain et al 2006), with the exception of p.N225S.…”

Section: Introductionmentioning

confidence: 99%

A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency

et al. 2010

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Heterozygous mutations of the gene encoding transcription factor OTX2 were recently shown to be responsible for ocular as well as pituitary abnormalities. Here, we describe a patient with unilateral anophthalmia and short stature. Endocrine evaluation of the hypothalamic-pituitary axis revealed isolated growth hormone deficiency (IGHD) with small anterior pituitary gland, invisible stalk, ectopic posterior lobe, and right anophthalmia on brain magnetic resonance imaging. DNA was analyzed for mutations in the HESX1, SOX2, and OTX2 genes. Molecular analysis yielded a novel heterozygous OTX2 mutation (c.270A>T, p.R90S) within the homeodomain. Functional analysis revealed that the mutation inhibited both the DNA binding and transactivation activities of the protein. This novel loss-of-function mutation is associated with anophthalmia and IGHD in a patient of Sephardic Jewish descent. We recommend that patients with GH deficiency and ocular malformation in whom genetic analysis for classic transcription factor genes (PROP1, POU1F1, HESX1, and LHX4) failed to identify alterations should be checked for the presence of mutations in the OTX2 gene.

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“…Importantly, OTX-2 has been shown to be expressed in GnRH neurons and has also shown to be upregulated during GnRH neuronal development [43,44]. The vital importance of OTX-2 in GnRH neurons is underscored in mutations of OTX-2 being associated with human hypogonotropic hypogonadism [45][46][47]. Additionally, deletion of OTX-2 in GnRH neurons of mice results in a significant decrease in the number of GnRH neurons in the hypothalamus, with delay in pubertal onset, abnormal estrous cyclicity, and infertility in the GnRH neuron-specific Otx-2 KO (GnRH-Otx2KO) mice [44].…”

Section: Discussionmentioning

confidence: 99%

Kisspeptin Induces Dynamic Chromatin Modifications to Control GnRH Gene Expression

2015

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In vitro studies have demonstrated an increase in GnRH gene expression associated with an elevated secretory response to kisspeptin administration, suggesting that kisspeptin mediates GnRH expression at both the secretory and pretranslational levels. However, the kisspeptin-mediated intracellular mechanisms associated with the dynamic chromatin modifications modulating GnRH gene expression are unclear. The studies in this manuscript describe specific histone modifications on the enhancer and promoter of the mouse GnRH (mGnRH) gene induced by kisspeptin in GnRH neuronal cell lines (GT1-7 cells). ChIP assays followed by quantitative real-time PCR (qPCR) demonstrate that 15 and 45 min of 10(-9) M kisspeptin significantly increased histone 3 acetylation (H3Ac) at the kisspeptin response element (KsRE) contained between -3446 and -2806 bp of the mGnRH enhancer (GnRHen) in GT1-7 cells, while no changes were observed in the downstream neuron-specific element (NSE). Moreover, kisspeptin specifically induced acetylation of H3AcK14 and K27 and trimethylation of H3 lysine 4 at the KsRE (markers of active chromatin) and no changes in dimethylation of H3K9 (a marker associated with gene repression). Occupancy of RNA Pol II (RNAPII) and a differential carboxyl-terminal domain (CTD) phosphorylation pattern was observed. An interaction between the NSE and the KsRE via a chromatin loop in the mGnRH gene by kisspeptin was detected by the chromosome conformation capture assay (3C). In conclusion, these results demonstrate that kisspeptin induces histone acetylation/methylation and consequently enhances the formation of a chromatin loop in the mGnRH gene which results in known increase in kisspeptin-dependent mGnRH expression.

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Heterozygous Orthodenticle Homeobox 2 Mutations Are Associated with Variable Pituitary Phenotype

Cited by 21 publications

References 0 publications

Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies

Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies

A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency

Kisspeptin Induces Dynamic Chromatin Modifications to Control GnRH Gene Expression

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