scholarly journals Commentary: Novel mechanism of pituitary hormone deficiency: genetic variants shift splicing to produce a dominant negative transcription factor isoform

2021 ◽  
Author(s):  
Thierry Brue ◽  
Sally Camper
Keyword(s):  
Transcription Factor ◽  
Alternative Splicing ◽  
Molecular Diagnosis ◽  
Genetic Variants ◽  
Dominant Negative ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Over Expression ◽  
Combined Pituitary Hormone Deficiency

Recent studies have shown a novel mechanism of combined pituitary hormone deficiency associated with mutations in POU1F1, altering the balance of alternative-splicing, which results in over-expression of the beta isoform of POU1F1. These studies underscore the need for biologists, in the context of the routine molecular diagnosis of this condition, to investigate alternative splicing in POU1F1 as well as in other genes.

scholarly journals Novel Mutations within the POU1F1 Gene Associated with Variable Combined Pituitary Hormone Deficiency

2005 ◽  
Vol 90 (8) ◽  
pp. 4762-4770 ◽  
Author(s):  
James P. G. Turton ◽  
Rachel Reynaud ◽  
Ameeta Mehta ◽  
John Torpiano ◽  
Alexandru Saveanu ◽  
...  
Keyword(s):  
Dna Binding ◽  
Mutational Analysis ◽  
Hot Spot ◽  
Dominant Negative ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Novel Mutations ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Functional Studies

Context: Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin, and TSH deficiency. Objective: We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1. Results: Causative mutations were identified in 10 of 129 individuals (7.8%). Of these, five patients harbored the dominant negative R271W mutation, which is a well-recognized mutational hot spot. We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single base pair (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA binding and a reduction in transactivation. Conclusions: Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in three patients who were diagnosed as having ACTH deficiency but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement that had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD.

scholarly journals OTX2 Loss of Function Mutation Causes Anophthalmia and Combined Pituitary Hormone Deficiency with a Small Anterior and Ectopic Posterior Pituitary

2009 ◽  
Vol 94 (1) ◽  
pp. 314-319 ◽  
Author(s):  
Toshihiro Tajima ◽  
Akira Ohtake ◽  
Masaya Hoshino ◽  
Shin Amemiya ◽  
Nozomu Sasaki ◽  
...  
Keyword(s):  
Brain Magnetic Resonance Imaging ◽  
Dominant Negative ◽  
Hormone Deficiency ◽  
Dominant Negative Effect ◽  
Pituitary Hormone ◽  
Posterior Lobe ◽  
Loss Of Function ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Negative Effect

Abstract Context: Orthodenticle homeobox 2 (OTX2) is a transcription factor necessary for ocular and forebrain development. In humans, heterozygous mutations of OTX2 cause severe ocular malformations. However, whether mutations of OTX2 cause pituitary structural abnormalities or combined pituitary hormone deficiency (CPHD) has not been clarified. Objectives: We surveyed the functional consequences of a novel OTX2 mutation that was detected in a patient with anophthalmia and CPHD. Patient: We examined a Japanese patient with growth disturbance, anophthalamia, and severe developmental delay. He showed deficiencies in GH, TSH, LH, FSH, and ACTH. Brain magnetic resonance imaging revealed a small anterior pituitary gland, invisible stalk, ectopic posterior lobe, and Chiari malformation. Results: Sequence analysis of OTX2 demonstrated a heterozygous two bases insertion [S136fsX178 (c.576-577insCT)] in exon 3. The mutant Otx2 protein localized to the nucleus, but did not activate the promoter of the HESX1 and POU1F1 gene, indicating a loss of function mutation. No dominant negative effect in the presence of wild-type Otx2 was observed. Conclusion: This case indicates that the OTX2 mutation is a cause of CPHD. Further study of more patients with OTX2 defects is necessary to clarify the clinical phenotypes and endocrine defects caused by OTX2 mutations.

scholarly journals Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

2007 ◽  
Vol 51 (7) ◽  
pp. 1097-1103 ◽  
Author(s):  
Teresa C. Vieira ◽  
Valter T. Boldarine ◽  
Julio Abucham
Keyword(s):  
Transcription Factor ◽  
High Frequency ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Posterior Pituitary ◽  
Developmental Gene ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Prevalent Disease ◽  
Genetic Form

Combined Pituitary Hormone Deficiency (CPHD) is a prevalent disease in Neuroendocrinology services. The genetic form of CPHD may originate from mutations in pituitary transcription factor (PTF) genes and the pituitary image in these cases may give a clue of what PTF is most probably mutated: defects in LHX4 are usually associated with ectopic posterior pituitary (EPP); defects in LHX3, PIT1, and PROP1, with normally placed posterior pituitary (NPPP); HESX1 mutations are associated with both. OBJECTIVE: To identify mutations in PTF genes in patients with idiopathic hypopituitarism followed in our service, based on the presence or absence of EPP on sellar MRI. METHODS: Forty patients with idiopathic hypopituitarism (36 families, 9 consanguineous), followed in the Neuroendocrinology Outpatient Clinic of UNIFESP, Brazil, were submitted to sequencing analyses of PTF genes as follows: LHX3, HESX1, PIT1, and PROP1 were sequenced in patients with NPPP (26/40) and HESX1 and LHX4 in patients with EPP (14/40). RESULTS: We identified only PROP1 mutations in 9 out of 26 patients with CPHD and NPPP (35%). Since eight of them came from 4 consanguineous families, the prevalence of PROP1 mutations was higher when only consanguineous families were considered (44%, 4/9). At the end of the study, we decided to sequence PROP1 in patients with EPP, just to confirm that they were not candidates for PROP1 mutations. No patients with EPP had PROP1 or other PTF mutations. CONCLUSIONS: Patients with idiopathic CPHD and NPPP, born from consanguineous parents, are the strong candidates for PROP1 mutations. Other developmental gene(s) may be involved in the genesis of idiopathic hypopituitarism associated with EPP.

scholarly journals A novel OTX2 mutation in a patient with combined pituitary hormone deficiency, pituitary malformation, and an underdeveloped left optic nerve

2012 ◽  
Vol 167 (3) ◽  
pp. 441-452 ◽  
Author(s):  
Darya Gorbenko Del Blanco ◽  
Christopher J Romero ◽  
Daniel Diaczok ◽  
Laura C G de Graaff ◽  
Sally Radovick ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mutation Screening ◽  
Genetic Alterations ◽  
Dominant Negative ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Coding Regions ◽  
Dominant Negative Inhibitor

Orthodenticle homolog 2 (OTX2) is a homeobox family transcription factor required for brain and eye formation. Various genetic alterations in OTX2 have been described, mostly in patients with severe ocular malformations. In order to expand the knowledge of the spectrum of OTX2 mutation, we performed OTX2 mutation screening in 92 patients with combined pituitary hormone deficiency (CPHD). We directly sequenced the coding regions and exon–intron boundaries of OTX2 in 92 CPHD patients from the Dutch HYPOPIT study in whom mutations in the classical CPHD genes PROP1, POU1F1, HESX1, LHX3, and LHX4 had been ruled out. Among 92 CPHD patients, we identified a novel heterozygous missense mutation c.401C>G (p.Pro134Arg) in a patient with CPHD, pituitary malformation, and an underdeveloped left optic nerve. Binding of both the wild-type and mutant OTX2 proteins to bicoid binding sites was equivalent; however, the mutant OTX2 exhibited decreased transactivation. We describe a novel missense heterozygous OTX2 mutation that acts as a dominant negative inhibitor of target gene expression in a patient with CPHD, pituitary malformation, and optic nerve hypoplasia. We provide an overview of all OTX2 mutations described till date, which show that OTX2 is a promising candidate gene for genetic screening of patients with CPHD or isolated GH deficiency (IGHD). As the majority of the OTX2 mutations found in patients with CPHD, IGHD, or short stature have been found in exon 5, we recommend starting mutational screening in those patients in exon 5 of the gene.

LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes

Gene ◽  
2001 ◽  
Vol 265 (1-2) ◽  
pp. 61-69 ◽  
Author(s):  
Kyle W. Sloop ◽  
Gretchen E. Parker ◽  
Kimberly R. Hanna ◽  
Heather A. Wright ◽  
Simon J. Rhodes
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency
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