scholarly journals Congenital Hypopituitarism: Various Genes, Various Phenotypes

2019 ◽  
Vol 51 (02) ◽  
pp. 81-90 ◽  
Author(s):  
Maria Xatzipsalti ◽  
Antonis Voutetakis ◽  
Lela Stamoyannou ◽  
George Chrousos ◽  
Christina Kanaka-Gantenbein
Keyword(s):  
Transcription Factors ◽  
Gene Mutations ◽  
Pituitary Hormones ◽  
Genetic Mutations ◽  
Murine Models ◽  
Spontaneous Mutations ◽  
Complex Disorders ◽  
Complex Process ◽  
Transgenic Murine Models ◽  
Congenital Hypopituitarism

AbstractThe ontogenesis and development of the pituitary gland is a highly complex process that depends on a cascade of transcription factors and signaling molecules. Spontaneous mutations and transgenic murine models have demonstrated a role for many of these factors, including HESX1, PROP1, PIT1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, SHH, GLI2, and FGF8 in the etiology of congenital hypopituitarism. Genetic mutations in any of these factors can lead to congenital hypopituitarism, which is characterized by the deficiency in one or more pituitary hormones. The phenotype can be highly variable, consisting of isolated hypopituitarism or more complex disorders. The same phenotype can be attributed to different gene mutations; while a given gene mutation can induce different phenotypes. This review highlights the genetic variations that lead to congenital hypopituitarism and their associated defects. The overall incidence of mutations in known transcription factors in patients with hypopituitarism is low; therefore many gene mutations or even gene- epigenetic interactions have to be unraveled in the future to explain the vast majority of still unclear cases of congenital hypopituitarism.

scholarly journals Hypothalamic and pituitary development: novel insights into the aetiology

2007 ◽  
Vol 157 (suppl_1) ◽  
pp. S3-S14 ◽  
Author(s):  
Daniel Kelberman ◽  
Mehul Tulsidas Dattani
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Cell Types ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Gene Encoding ◽  
Complex Disorders ◽  
Signalling Molecules ◽  
Pituitary Development ◽  
Transgenic Murine Models

The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and the characterization of these will further elucidate the pathogenesis of these complex conditions and also shed light on normal pituitary development.

scholarly journals Remodeling Alzheimer-amyloidosis models by seeding

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Brittany S. Ulm ◽  
David R. Borchelt ◽  
Brenda D. Moore
Keyword(s):  
Amyloid Precursor Protein ◽  
Neurodegenerative Diseases ◽  
Amyloid Beta ◽  
Precursor Protein ◽  
Time Interval ◽  
Murine Models ◽  
Brain Pathology ◽  
Amyloid Deposits ◽  
Transgenic Murine Models ◽  
Mutant Genes

AbstractAlzheimer’s disease (AD) is among the most prevalent neurodegenerative diseases, with brain pathology defined by extracellular amyloid beta deposits and intracellular tau aggregates. To aid in research efforts to improve understanding of this disease, transgenic murine models have been developed that replicate aspects of AD pathology. Familial AD is associated with mutations in the amyloid precursor protein and in the presenilins (associated with amyloidosis); transgenic amyloid models feature one or more of these mutant genes. Recent advances in seeding methods provide a means to alter the morphology of resultant amyloid deposits and the age that pathology develops. In this review, we discuss the variety of factors that influence the seeding of amyloid beta pathology, including the source of seed, the time interval after seeding, the nature of the transgenic host, and the preparation of the seeding inoculum.

scholarly journals Comparison of 10 murine models reveals a distinct biomechanical phenotype in thoracic aortic aneurysms

2017 ◽  
Vol 14 (130) ◽  
pp. 20161036 ◽  
Author(s):  
C. Bellini ◽  
M. R. Bersi ◽  
A. W. Caulk ◽  
J. Ferruzzi ◽  
D. M. Milewicz ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Structural Integrity ◽  
Ascending Aorta ◽  
Elastic Fibre ◽  
Cytoskeletal Proteins ◽  
Aortic Aneurysms ◽  
Genetic Mutations ◽  
Murine Models ◽  
Thoracic Aortic Aneurysms ◽  
Signalling Molecules

Thoracic aortic aneurysms are life-threatening lesions that afflict young and old individuals alike. They frequently associate with genetic mutations and are characterized by reduced elastic fibre integrity, dysfunctional smooth muscle cells, improperly remodelled collagen and pooled mucoid material. There is a pressing need to understand better the compromised structural integrity of the aorta that results from these genetic mutations and renders the wall vulnerable to dilatation, dissection or rupture. In this paper, we compare the biaxial mechanical properties of the ascending aorta from 10 murine models: wild-type controls, acute elastase-treated, and eight models with genetic mutations affecting extracellular matrix proteins, transmembrane receptors, cytoskeletal proteins, or intracellular signalling molecules. Collectively, our data for these diverse mouse models suggest that reduced mechanical functionality, as indicated by a decreased elastic energy storage capability or reduced distensibility, does not predispose to aneurysms. Rather, despite normal or lower than normal circumferential and axial wall stresses, it appears that intramural cells in the ascending aorta of mice prone to aneurysms are unable to maintain or restore the intrinsic circumferential material stiffness, which may render the wall biomechanically vulnerable to continued dilatation and possible rupture. This finding is consistent with an underlying dysfunctional mechanosensing or mechanoregulation of the extracellular matrix, which normally endows the wall with both appropriate compliance and sufficient strength.

scholarly journals Genetic diagnosis of congenital hypopituitarism by a target gene panel: novel pathogenic variants in GLI2, OTX2 and GHRHR

2019 ◽  
Vol 8 (5) ◽  
pp. 590-595 ◽  
Author(s):  
Marilena Nakaguma ◽  
Fernanda A Correa ◽  
Lucas S Santana ◽  
Anna F F Benedetti ◽  
Ricardo V Perez ◽  
...  
Keyword(s):  
Target Gene ◽  
Gh Deficiency ◽  
Massively Parallel Sequencing ◽  
Genetic Diagnosis ◽  
Pituitary Hormones ◽  
Gene Panel ◽  
Massively Parallel ◽  
Parallel Sequencing ◽  
Pathogenic Variants ◽  
Congenital Hypopituitarism

Aim Congenital hypopituitarism has an incidence of 1:3500–10,000 births and is defined by the impaired production of pituitary hormones. Early diagnosis has an impact on management and genetic counselling. The clinical and genetic heterogeneity of hypopituitarism poses difficulties to select the order of genes to analyse. The objective of our study is to screen hypopituitarism genes (candidate and previously related genes) simultaneously using a target gene panel in patients with congenital hypopituitarism. Methods Screening of 117 subjects with congenital hypopituitarism for pathogenic variants in 26 genes associated with congenital hypopituitarism by massively parallel sequencing using a customized target gene panel. Results We found three novel pathogenic variants in OTX2 c.295C>T:p.Gln99*, GLI2 c.1681G>T:p.Glu561* and GHRHR c.820_821insC:p.Asp274Alafs*113, and the previously reported variants in GHRHR c.57+1G>A and PROP1 [c.301_302delAG];[c.109+1G>A]. Conclusions Our results indicate that a custom-designed panel is an efficient method to screen simultaneously variants of biological and clinical relevance for congenital GH deficiency. A genetic diagnosis was possible in 5 out of 117 (4%) patients of our cohort. We identified three novel pathogenic variants in GHRHR, OTX2 and GLI2 expanding the spectrum of variants associated with congenital hypopituitarism.

Pulmonary hypertension genes as major diagnostic tools

ESC CardioMed ◽  
2018 ◽  
pp. 2490-2493
Author(s):  
Mélanie Eyries ◽  
Barbara Girerd ◽  
David Montani ◽  
David-Alexandre Tregouët ◽  
Marc Humbert ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Gene Mutations ◽  
Diagnostic Tools ◽  
Genetic Mutations ◽  
Incomplete Penetrance ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Sporadic Cases ◽  
Pulmonary Arterial

A few genes have been shown to be major predisposing factors for pulmonary hypertension and are responsible for heritable forms of the disease. However, for nearly all genes described, not all mutation carriers develop the disease (autosomal transmission with incomplete penetrance) explaining the presence of genetic mutations in apparently sporadic cases. Beside mutations in major genes (BMPR2 for pulmonary arterial hypertension and EIF2AK4 for recessive heritable pulmonary veno-occlusive disease), other genes have been involved in a very limited number of cases (KCNK3, CAV1, and Smad8). Gene mutations are also been found as part of syndromic diseases (ACVRL1 mutations in hereditary haemorrhagic telangiectasia and TBX4 in small patella syndrome).

scholarly journals Androgenic potential of human fetal adrenals at the end of the first trimester

2017 ◽  
Vol 6 (6) ◽  
pp. 348-359 ◽  
Author(s):  
I Savchuk ◽  
M L Morvan ◽  
J P Antignac ◽  
K Gemzell-Danielsson ◽  
B Le Bizec ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Gas Chromatography ◽  
Transcription Factors ◽  
Western Blotting ◽  
Adrenal Glands ◽  
First Trimester ◽  
Gas Chromatography Mass Spectrometry ◽  
Steroidogenic Enzymes ◽  
Complex Process ◽  
Low Expression

The onset of steroidogenesis in human fetal adrenal glands (HFA) during the first trimester is poorly investigated. An unresolved question is the capacity of the HFA to produce potent androgen DHT via conventional and/or the backdoor pathway(s) at the end of first trimester, when androgen-responsive organs are developed. Our aim was to explore steroidogenesis and the expression of steroidogenic enzymes and transcription factors in HFA at gestational weeks (GW) 9–12 with focus on their androgenic potential. Steroids in the HFA were analyzed by gas chromatography/mass spectrometry. The expression of steroidogenic enzymes and transcription factors in the HFA at GW9–12 was investigated by qPCR, automated Western blotting and immunohistochemistry. We demonstrated that during GW9–12 HFA produced steroids of the ∆5, ∆4 and the backdoor pathways of the biosynthesis of DHT, though the latter was limited to production of 17α-OH-dihydroprogesterone, androsterone and androstanedione without further conversion to DHT. The only androgens identified in the HFA were testosterone and androsterone, a precursor in the biosynthesis of DHT. We also observed higher levels of CYP17A1 but low expression of 3βHSD2 at GW11–12 in the HFA. Elevated levels of CYP17A1 were associated with an increased expression of SF-1 and GATA-6. Altogether, our data demonstrate that of those steroids analyzed, the only potent androgen directly produced by the HFA at GW9–12 was testosterone. The onset of steroidogenesis in the HFA is a complex process that is regulated by the coordinated action of related transcription factors.

scholarly journals A Rare Corticotroph-Secreting Tumor with Coexisting Prolactin and Growth Hormone Staining Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Subramanian Kannan ◽  
Susan M. Staugaitis ◽  
Robert J. Weil ◽  
Betul Hatipoglu
Keyword(s):  
Growth Hormone ◽  
Transcription Factors ◽  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Rare Case ◽  
Pituitary Hormones ◽  
Review Literature ◽  
Pituitary Cells ◽  
Biological Mechanisms

Pituitary adenomas can express and secrete different hormones. Expression of pituitary hormones in nonneoplastic pituitary cells is regulated by different transcription factors. Some pituitary adenomas show plurihormonal expression. The most commonly reported plurihormonal adenomas are composed of somatotrophs, lactotrophs, thyrotrophs and gonadotrophs. Pituitary adenomas composed of both corticotroph and somatolactotroph secreting cells are not common because transcription factors regulating the expression of these hormones are different. We report a rare case of pituitary adenoma with concomitant corticotroph, prolactin, and growth hormone staining cells, review literature on similar cases, and discuss possible biological mechanisms underlying these plurihormonal tumors.

scholarly journals Neonatal hypoglycemia in the De Morsier syndrome

2018 ◽  
Vol 64 (1) ◽  
pp. 42-44
Author(s):  
Tatiana V. Kovalenko ◽  
Irina N. Petrova ◽  
Tatiana Yu. Tarasova
Keyword(s):  
Gene Mutations ◽  
Severe Hypoglycemia ◽  
Endocrine Disorders ◽  
Free T4 ◽  
Gene Encoding ◽  
Oculomotor Disturbances ◽  
De Morsier Syndrome ◽  
Muscle Hypotonia ◽  
Congenital Hypopituitarism ◽  
Relationship Of

The article discusses the causes and diagnostic criteria of the septo-optic dysplasia or De Morsier syndrome. De Morsier syndrome attracts attention of endocrinologists due to the development secondary hypofunction of the endocrine glands and somatotropic deficiency associated with this disease. Septo-optic dysplasia is a polyetiologic disease. The relationship of the disease with the antenatal influence of alcohol, narcotic substances, neurotropic drugs, significant perinatal infections, maternal endocrine diseases, gene mutations, in particular, mutations in the HESX1 gene, encoding the pituitary transcription factors involved in the embryogenesis of the adenohypophysis. We report a clinical case of the disease accompanied by congenital hypopituitarism symptoms. The disease manifested in the neonatal period. The child had severe hypoglycemia in combination with neurological symptoms in the form muscle hypotonia and oculomotor disturbances. The diagnosis of the De Morsier syndrome was verified by the results of MRI of the brain. Endocrine disorders in this patient were characterized by low levels of ACTH, cortisol, IGF-1, and free T4. The administered therapy corrected endocrine disorders in the child. In summary, septo-optic dysplasia or De Morsier syndrome is the subject to interdisciplinary attention of neonatologists, endocrinologists, neurologists, optometrists, and geneticists.

scholarly journals Metabolic Convergence on Lipogenesis in RAS, BCR-ABL, and MYC-driven Lymphoid Malignancies

2020 ◽  
Author(s):  
Daniel Liefwalker ◽  
Meital Ryan ◽  
Ian Lai ◽  
Adriane Mosley ◽  
Gabrielle Dewson ◽  
...  
Keyword(s):  
Cell Lines ◽  
Human Subjects ◽  
Trial Registration ◽  
Metabolic Profiles ◽  
Murine Models ◽  
Clinical Interventions ◽  
Lymphoid Malignancies ◽  
Transgenic Murine Models

Abstract Background Metabolic re-programming is a central feature in many cancer subtypes and a hallmark of cancer. Many therapeutic strategies attempt to exploit this feature, although often having unintended side effects on normal metabolic programs and limited efficacy due to integrative nature of metabolic substrate sourcing. Although the initiating oncogenic lesion may vary, in lymphoid malignancies tumor cells often share similar environments and potentially similar metabolic profiles. Methods We searched publicly available data sets for common metabolic convergence in lymphoma and leukemia. Using in vitro cell lines derived in from conditional MYC, RAS, and BCR-ABL transgenic murine models we examine metabolic profiles of lipogenesis. We then utilize preclinical murine models and transgenic primary model of T-ALL to determine the effect of lipogenesis blockade across BCR-ABL, RAS, and c-MYC-driven lymphoid malignancies. Statistical significance was calculated using unpaired T tests and one-way ANOVA. Results We find that de novo lipid biogenesis is a shared feature of several lymphoma subtypes. Using cell lines derived in from conditional MYC, RAS, and BCR-ABL transgenic murine models we demonstrate shared responses to inhibition of lipogenesis by the acetyl-coA carboxylase inhibitor 5-(Tetradecloxy)-2-furic Acid (TOFA). We identify specific cell death responses to TOFA in vitro and in vivo and demonstrate delayed engraftment and progression in vivo in transplanted lymphoma cell lines. We also observed delayed progression of T-ALL in a primary transgenic mouse model upon TOFA administration. In a panel of human cell lines, we demonstrate sensitivity to TOFA treatment as a feature of MYC high expressing lymphoma cell lines. Conclusions These studies indicate that inhibition of lipogenesis may be a common survival strategy for many lymphomas and that high MYC expression is predictive of sensitivity to blockade of fatty acid synthesis. Trial Registration This study does not include any clinical interventions on human subjectsTrial RegistrationThis study does not include any clinical interventions on human subjects

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