Gradual Loss of ACTH Due to a Novel Mutation in LHX4: Comprehensive Mutation Screening in Japanese Patients with Congenital Hypopituitarism

Takagi, Masaki; Ishii, Tomohiro; Inokuchi, Mikako; Amano, Nobuyuki; Narumi, Shunji; Asakura, Yumi; Muroya, Koji; Hasegawa, Yukihiro; Adachi, Masanori; Hasegawa, Tomonobu

doi:10.1371/journal.pone.0046008

Cited by 27 publications

(21 citation statements)

References 24 publications

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“…In all the patients, mutations in POU1F1, PROP1, HESX1, LHX3, LHX4, OTX2, SOX2, SOX3, and GLI2 have been excluded by PCR-based sequencing (4). Gene copy number aberrations in POU1F1, PROP1, HESX1, LHX3, and LHX4 were also excluded by multiplex ligation-dependent probe amplification (MLPA) analyses (4). Approval for this study was obtained from the Institutional Review Board of Keio University School of Medicine.…”

Section: Subjectsmentioning

confidence: 99%

“…Echocardiogram revealed a patent ductus arteriosus, which was surgically corrected at 1 month of age. At the age of 1 year, he was diagnosed with central hypothyroidism with a low fT 4 Table 4, see section on supplementary data given at the end of this article). The brain MRI exhibited anterior pituitary hypoplasia, visible but thin stalk, and EPP (Fig.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

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Heterozygous defects in PAX6 gene and congenital hypopituitarism

Takagi

Nagasaki

Fujiwara

et al. 2015

European Journal of Endocrinology

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Background: The prevalence of congenital hypopituitarism (CH) attributable to known transcription factor mutations appears to be rare and other causative genes for CH remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements could be one of the molecular mechanisms participating in its etiology, especially in syndromic cases. Objective: To identify the role of copy number variations (CNVs) in the etiology of CH and to identify novel genes implicated in CH. Subjects and methods: We enrolled 88 (syndromic: 30; non-syndromic: 58) Japanese CH patients. We performed an array comparative genomic hybridization screening in the 30 syndromic CH patients. For all the 88 patients, we analyzed PAX6 by PCR-based sequencing. Results: We identified one heterozygous 310-kb deletion of the PAX6 enhancer region in one patient showing isolated GH deficiency (IGHD), cleft palate, and optic disc cupping. We also identified one heterozygous 6.5-Mb deletion encompassing OTX2 in a patient with bilateral anophthalmia and multiple pituitary hormone deficiency. We identified a novel PAX6 mutation, namely p.N116S in one non-syndromic CH patient showing IGHD. The p.N116S PAX6 was associated with an impairment of the transactivation capacities of the PAX6-binding elements. Conclusions: This study showed that heterozygous PAX6 mutations are associated with CH patients. PAX6 mutations may be associated with diverse clinical features ranging from severely impaired ocular and pituitary development to apparently normal phenotype. Overall, this study identified causative CNVs with a possible role in the etiology of CH in !10% of syndromic CH patients.

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Section: Subjectsmentioning

confidence: 99%

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Heterozygous defects in PAX6 gene and congenital hypopituitarism

Takagi

Nagasaki

Fujiwara

et al. 2015

European Journal of Endocrinology

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“…Previous studies have shown that GH and PRL cells may be inter-changeable, as progenitors may differentiate into GH, which is later transformed into PRL (Di Iorgi et al, 2012a;Tsai et al, 2012). Recent studies in fish and birds have supported the theory that PRL and GH follow an independent differentiation (Jagtap et al, 2012;Takagi et al, 2012). Other studies, however, did not detect the expression of PRL in the embryonic pituitary (Garcia Martin et al, 2010;Sukhija et al, 2012).…”

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confidence: 99%

Effect of transcription factor ZBTB20 on mouse pituitary development

Dong

Chen

2015

Genet. Mol. Res.

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ABSTRACT. Pituitary, a critical component in the neuroendocrine system, plays an indispensable role in the regulation of body growth. The transcriptional factor ZBTB20 is widely expressed in brain tissues and participates in hippocampal development; however, the detailed molecular mechanism remains unknown. Therefore, the aim of this study was to investigate the effect of ZBTB20 on mouse pituitary development and related mechanisms in ZBTB20 gene knockout mice. The expressional profiles of ZBTB20 in various neuroendocrinal cells during the different developmental stages (from E10 to P0) were described by immunofluorescence staining. A ZBTB20 gene knockout mouse model was then generated. Real-time polymerase chain reaction and western blotting assays were used to detect the levels of five hormones: growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroidstimulating hormone (TSH). ZBTB20 protein expression was identified from E14 until birth. A majority of the pituitary endocrinal cells were ZBTB20-positive. In ZBTB20 knockout mice, the level of GH decreased by half and PRL expression was eliminated. No significant change was observed in the other three hormones (LH, FSH, and TSH). ZBTB20, an important transcriptional factor in pituitary development, is mainly responsible for the 17623 ZBTB20 regulates pituitary development ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 17622-17629 (2015) terminal differentiation of prolactin-secreting cells, thereby regulating the secretion of the pituitary hormones.

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“…Agenesis or hypoplasia of the ICA is a rare vascular anomaly seen in about 0.01% of the population [10]. Twelve cases of agenesis of the ICA accompanied by CPHD have been reported so far [8,11,12,13,14,15,16,17,18,19,20,21].…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation in <b><i>OTX2</i></b> Causes Combined Pituitary Hormone Deficiency, Bilateral Microphthalmia, and Agenesis of the Left Internal Carotid Artery

et al. 2016

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Background: Mutations in OTX2 cause hypopituitarism, ranging from isolated growth hormone deficiency to combined pituitary hormone deficiency (CPHD), which are commonly detected in association with severe eye abnormalities, including anophthalmia or microphthalmia. Pituitary phenotypes of OTX2 mutation carriers are highly variable; however, ACTH deficiency during the neonatal period is not common in previous reports. Objective: We report a novel missense OTX2 (R89P) mutation in a CPHD patient with severe hypoglycemia in the neonatal period due to ACTH deficiency, bilateral microphthalmia, and agenesis of the left internal carotid artery (ICA). Results: We identified a novel heterozygous mutation in OTX2 (c.266G>C, p.R89P). R89P OTX2 showed markedly reduced transcriptional activity of HESX1 and POU1F1 reporters compared with wild-type OTX2. A dominant negative effect was noted only in the transcription analysis with POU1F1 promoter. Electrophoretic mobility shift assay experiments showed that R89P OTX2 abrogated DNA-binding ability. Conclusion:OTX2 mutations can cause ACTH deficiency in the neonatal period. Our study also shows that OTX2 mutations are associated with agenesis of the ICA. To the best of our knowledge, this is the first report of a transcription factor gene mutation, which was identified due to agenesis of the ICA of a patient with CPHD. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in OTX2.

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Gradual Loss of ACTH Due to a Novel Mutation in LHX4: Comprehensive Mutation Screening in Japanese Patients with Congenital Hypopituitarism

Cited by 27 publications

References 24 publications

Heterozygous defects in PAX6 gene and congenital hypopituitarism

Heterozygous defects in PAX6 gene and congenital hypopituitarism

Effect of transcription factor ZBTB20 on mouse pituitary development

A Novel Mutation in <b><i>OTX2</i></b> Causes Combined Pituitary Hormone Deficiency, Bilateral Microphthalmia, and Agenesis of the Left Internal Carotid Artery

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