The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Ruiqin Zhong - One of the best experts on this subject based on the ideXlab platform.
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amphivasal vascular bundle 1 a gain of function Mutation of the ifl1 rev gene is associated with alterations in the polarity of leaves stems and carpels
Plant and Cell Physiology, 2004Co-Authors: Ruiqin Zhong, Zhenghua YeAbstract:In Arabidopsis stems, the vascular bundles in the stele are arranged in a ring-like pattern and the vascular tissues in each bundle are organized in a collateral pattern. We have shown previously that the semidominant amphivasal vascular bundle I (avb1) Mutation transforms the collateral vascular bundles into amphivasal bundles and disrupts the ring-like arrangement of vascular bundles in the stele. In this study, we show that the avbl Mutation occurred in the putative microRNA 165 target sequence in the IFL1/REV gene and caused an amino acid substitution in the putative sterol/lipid-binding START domain. We present direct evidence that the wild-type IFL1/REV mRNA was cleaved within the microRNA 165 target sequence and the avb1 Mutation resulted in an inhibition of cleavage and a higher level accumulation of full-length mRNA, suggesting a role of microRNA 165 in the regulation of IFL1/REV gene expression. In addition to an alteration in vascular patterning, the avbl Mutation also caused dramatic changes in fiber cell wall thickening and organ polarity, including aberrant formation and proliferation of cauline leaves and branches, production of trumpet-shaped leaves with reversed adaxial-abaxial identity, ectopic growth of carpel-like structures on the outer surface of carpels, and fasciation of inflorescence. Ectopic overexpression of the avbl mutant cDNA not only phenocopied most of the avbl mutant phenotypes but also led to additional novel phenotypes such as formation of leaves with extremely narrow blades and ectopic production of branches in the axil of siliques. Taken together, these results suggest that the avbl Gain-of-Function Mutation of the IFL1/REV gene alters the positional information that determines vascular patterning and organ polarity.
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amphivasal vascular bundle 1 a gain of function Mutation of the ifl1 rev gene is associated with alterations in the polarity of leaves stems and carpels
Plant and Cell Physiology, 2004Co-Authors: Ruiqin ZhongAbstract:In Arabidopsis stems, the vascular bundles in the stele are arranged in a ring-like pattern and the vascular tissues in each bundle are organized in a collateral pattern. We have shown previously that the semidominant amphivasal vascular bundle 1 (avb1) Mutation transforms the collateral vascular bundles into amphivasal bundles and disrupts the ring-like arrangement of vascular bundles in the stele. In this study, we show that the avb1 Mutation occurred in the putative microRNA 165 target sequence in the IFL1/REV gene and caused an amino acid substitution in the putative sterol/lipid-binding START domain. We present direct evidence that the wild-type IFL1/REV mRNA was cleaved within the microRNA 165 target sequence and the avb1 Mutation resulted in an inhibition of cleavage and a higher level accumulation of full-length mRNA, suggesting a role of microRNA 165 in the regulation of IFL1/REV gene expression. In addition to an alteration in vascular patterning, the avb1 Mutation also caused dramatic changes in fiber cell wall thickening and organ polarity, including aberrant formation and proliferation of cauline leaves and branches, production of trumpet-shaped leaves with reversed adaxial-abaxial identity, ectopic growth of carpel-like structures on the outer surface of carpels, and fasciation of inflorescence. Ectopic overexpression of the avb1 mutant cDNA not only phenocopied most of the avb1 mutant phenotypes but also led to additional novel phenotypes such as formation of leaves with extremely narrow blades and ectopic production of branches in the axil of siliques. Taken together, these results suggest that the avb1 Gain-of-Function Mutation of the IFL1/REV gene alters the positional information that determines vascular patterning and organ polarity.
Nikolay V Dokholyan - One of the best experts on this subject based on the ideXlab platform.
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gain of function Mutation w493r in the epithelial sodium channel allosterically reconfigures intersubunit coupling
Journal of Biological Chemistry, 2016Co-Authors: Mahmoud Shobair, Jack M Stutts, Onur Dagliyan, Pradeep Kota, Yan L Dang, Hong He, Nikolay V DokholyanAbstract:: Sodium absorption in epithelial cells is rate-limited by the epithelial sodium channel (ENaC) activity in lung, kidney, and the distal colon. Pathophysiological conditions, such as cystic fibrosis and Liddle syndrome, result from water-electrolyte imbalance partly due to malfunction of ENaC regulation. Because the quaternary structure of ENaC is yet undetermined, the bases of pathologically linked Mutations in ENaC subunits α, β, and γ are largely unknown. Here, we present a structural model of heterotetrameric ENaC α1βα2γ that is consistent with previous cross-linking results and site-directed mutagenesis experiments. By using this model, we show that the disease-causing Mutation αW493R rewires structural dynamics of the intersubunit interfaces α1β and α2γ. Changes in dynamics can allosterically propagate to the channel gate. We demonstrate that cleavage of the γ-subunit, which is critical for full channel activation, does not mediate activation of ENaC by αW493R. Our molecular dynamics simulations led us to identify a channel-activating electrostatic interaction between α2Arg-493 and γGlu-348 at the α2γ interface. By neutralizing a sodium-binding acidic patch at the α1β interface, we reduced ENaC activation of αW493R by more than 2-fold. By combining homology modeling, molecular dynamics, cysteine cross-linking, and voltage clamp experiments, we propose a dynamics-driven model for the Gain-of-Function in ENaC by αW493R. Our integrated computational and experimental approach advances our understanding of structure, dynamics, and function of ENaC in its disease-causing state.
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gain of function Mutation w493r in the epithelial sodium channel allosterically reconfigures intersubunit coupling
Journal of Biological Chemistry, 2016Co-Authors: Mahmoud Shobair, Jack M Stutts, Onur Dagliyan, Pradeep Kota, Yan L Dang, Nikolay V DokholyanAbstract:Sodium absorption in epithelial cells is rate-limited by the epithelial sodium channel (ENaC) activity in lung, kidney, and the distal colon. Pathophysiological conditions, such as cystic fibrosis and Liddle syndrome, result from water-electrolyte imbalance partly due to malfunction of ENaC regulation. Because the quaternary structure of ENaC is yet undetermined, the bases of pathologically linked Mutations in ENaC subunits α, β, and γ are largely unknown. Here, we present a structural model of heterotetrameric ENaC α1βα2γ that is consistent with previous cross-linking results and site-directed mutagenesis experiments. By using this model, we show that the disease-causing Mutation αW493R rewires structural dynamics of the intersubunit interfaces α1β and α2γ. Changes in dynamics can allosterically propagate to the channel gate. We demonstrate that cleavage of the γ-subunit, which is critical for full channel activation, does not mediate activation of ENaC by αW493R. Our molecular dynamics simulations led us to identify a channel-activating electrostatic interaction between α2Arg-493 and γGlu-348 at the α2γ interface. By neutralizing a sodium-binding acidic patch at the α1β interface, we reduced ENaC activation of αW493R by more than 2-fold. By combining homology modeling, molecular dynamics, cysteine cross-linking, and voltage clamp experiments, we propose a dynamics-driven model for the Gain-of-Function in ENaC by αW493R. Our integrated computational and experimental approach advances our understanding of structure, dynamics, and function of ENaC in its disease-causing state.
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w493r gain of function Mutation in atypical cystic fibrosis rewires the epithelial sodium channel dynamics
Biophysical Journal, 2015Co-Authors: Mahmoud Shobair, Yan H Dang, Jack M Stutts, Nikolay V DokholyanAbstract:Sodium absorption in epithelial cells is rate-limited by the epithelial sodium channel (ENaC) activity in lungs, kidney and the distal colon. Pathophysiological conditions, such as cystic fibrosis and Liddle syndrome, result from water-electrolyte imbalance partly due to malfunction of ENaC's molecular regulation. The molecular mechanism(s) of pathologically implicated Mutations in ENaC subunits are largely unknown due to absence of structural models for ENaC's oligomers. Here, we propose a dynamics-driven mechanism of the gain of function Mutation αW493R implicated in atypical cystic fibrosis. We utilize a combination of discrete molecular dynamics simulations (DMD) of the extracellular region of ENaC's heterotrimer αβγ and functional data from whole-cell electrophysiology experiments. Structure-function studies suggest that tetramers and trimers are the major characterized functional oligomeric states of ENaC. Using the crystal structure of the acid sensing ion channel, ENaC's structural homolog in the ENaC/degenerin mechanosensitive ion channel family, we have constructed homology models of ENaC subunits alpha, beta and gamma, in addition to the heterotrimers αβγ, αγβ and the heterotetramer αβαγ. Electrophysiology data show constitutive activity of αW493Rβγ in oocytes indicated by higher open probability and elevated basal activity compared to WT. Our DMD simulation provides an allosteric framework, which agrees with experimental data. W493R rewires the electrostatically mediated inter-residue interaction network in close proximity to W493, resulting in widening of the pore geometry in the outer mouth of the pore in the extracellular region. Rewiring effect of inter-residue interactions in 493R mutant pocket allosterically propagates across the channel resulting in a more stabilized global conformational ensemble of the channel. These findings predict a novel mechanism of ENaC's constitutive activity, in which changes in local dynamics can affect the relative population of the channel's active states and its open probability.
Pauline Dmitriev - One of the best experts on this subject based on the ideXlab platform.
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vascular changes in the retina and choroid of patients with epas1 gain of function Mutation syndrome
JAMA Ophthalmology, 2020Co-Authors: Pauline Dmitriev, Jared S Rosenblum, Herui Wang, Jing Cui, Tamara Prodanov, Alberto S Pappo, Mark R Gilbert, Gerard A Lutty, Chichao Chan, Emily Y ChewAbstract:Importance Patients with theEPAS1Gain-of-Function Mutation syndrome (or Pacak-Zhuang syndrome) present with multiple paragangliomas or pheochromocytomas, duodenal somatostatinoma, polycythemia, headaches, and sometimes diminished visual acuity at an early age. The characteristic phenotype and known genetic cause of the syndrome provide an opportunity to study the role of hypoxia-inducible factor 2α (HIF-2α) in oxygen sensing, development in regions of physiologic hypoxia, and other pathological processes. Objectives To describe the ocular lesions inEPAS1Gain-of-Function Mutation syndrome and to establish whether early-onset diminished visual acuity is developmental or associated with long-term physiologic sequelae of the syndrome. Design, Setting, and Participants This clinical case series with a transgenic murine model study was conducted from July 2013 to June 2019. Participants were 3 patients referred by their primary care physicians to the National Institutes of Health for evaluation of recurrent and metastatic paragangliomas or pheochromocytomas accompanied by polycythemia. The syndrome and somatic mosaicism in patients were confirmed by the identification of Gain-of-Function Mutations in theEPAS1gene in resected tumors and other tissues. Main Outcomes and Measures Ocular findings in patients withEPAS1Gain-of-Function Mutation syndrome. Results A total of 3 patients (mean [SD] age, 29 [6.2] years) with confirmed ocular abnormalities were included in the study. Increased contrast accumulation at the posterior aspect of the globe was seen bilaterally on magnetic resonance imaging scans in all patients. Ophthalmoscopy images demonstrated fibrosis overlying the optic disc, tortuous and dilated retinal vessels, and retinal pigment epithelium changes. Optic disc edema and retinal exudates were also seen. Fluorescein angiography images showed leakage of dye from postcapillary venules surrounding the optic disc and highlighted aberrant retinal vascular patterns. Enhanced-depth imaging optical coherence tomography images showed substantial thickening of the choroid and dilation of choroidal vessels. The ocular features of the syndrome were confirmed with a transgenic model of mice with Gain-of-FunctionEpas1A529VMutation. Conclusions and Relevance In this case series, HIF-2α and hypoxia signaling was found to have a role in vessel development within the choroid and retina, indicating that the marked permanent choroidal thickening and tortuous and dilated veins seen in the choroid and retina in patients withEPAS1Gain-of-Function Mutation syndrome were suggestive of the persistence of venous elements within the developing mesenchyme. These findings may explain other eye and vascular abnormalities whose pathogenesis remains unclear.
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a transgenic mouse model of pacak zhuang syndrome with an epas1 gain of function Mutation
Cancers, 2019Co-Authors: Herui Wang, Jared S Rosenblum, Ying Pang, Jing Cui, Chunzhang Yang, Qi Zhang, Qi Song, Francia Fang, Mitchell Sun, Pauline DmitrievAbstract:We previously identified a novel syndrome in patients characterized by paraganglioma, somatostatinoma, and polycythemia. In these patients, polycythemia occurs long before any tumor develops, and tumor removal only partially corrects polycythemia, with recurrence occurring shortly after surgery. Genetic mosaicism of Gain-of-Function Mutations of the EPAS1 gene (encoding HIF2α) located in the oxygen degradation domain (ODD), typically p.530–532, was shown as the etiology of this syndrome. The aim of the present investigation was to demonstrate that these Mutations are necessary and sufficient for the development of the symptoms. We developed transgenic mice with a Gain-of-Function Epas1A529V Mutation (corresponding to human EPAS1A530V), which demonstrated elevated levels of erythropoietin and polycythemia, a decreased urinary metanephrine-to-normetanephrine ratio, and increased expression of somatostatin in the ampullary region of duodenum. Further, inhibition of HIF2α with its specific inhibitor PT2385 significantly reduced erythropoietin levels in the mutant mice. However, polycythemia persisted after PT2385 treatment, suggesting an alternative erythropoietin-independent mechanism of polycythemia. These findings demonstrate the vital roles of EPAS1 Mutations in the syndrome development and the great potential of the Epas1A529V animal model for further pathogenesis and therapeutics studies.
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A Transgenic Mouse Model of Pacak–Zhuang Syndrome with An Epas1 Gain-of-Function Mutation
MDPI AG, 2019Co-Authors: Herui Wang, Jared S Rosenblum, Ying Pang, Jing Cui, Chunzhang Yang, Qi Zhang, Qi Song, Francia Fang, Mitchell Sun, Pauline DmitrievAbstract:We previously identified a novel syndrome in patients characterized by paraganglioma, somatostatinoma, and polycythemia. In these patients, polycythemia occurs long before any tumor develops, and tumor removal only partially corrects polycythemia, with recurrence occurring shortly after surgery. Genetic mosaicism of Gain-of-Function Mutations of the EPAS1 gene (encoding HIF2α) located in the oxygen degradation domain (ODD), typically p.530–532, was shown as the etiology of this syndrome. The aim of the present investigation was to demonstrate that these Mutations are necessary and sufficient for the development of the symptoms. We developed transgenic mice with a Gain-of-Function Epas1A529V Mutation (corresponding to human EPAS1A530V), which demonstrated elevated levels of erythropoietin and polycythemia, a decreased urinary metanephrine-to-normetanephrine ratio, and increased expression of somatostatin in the ampullary region of duodenum. Further, inhibition of HIF2α with its specific inhibitor PT2385 significantly reduced erythropoietin levels in the mutant mice. However, polycythemia persisted after PT2385 treatment, suggesting an alternative erythropoietin-independent mechanism of polycythemia. These findings demonstrate the vital roles of EPAS1 Mutations in the syndrome development and the great potential of the Epas1A529V animal model for further pathogenesis and therapeutics studies
Jared S Rosenblum - One of the best experts on this subject based on the ideXlab platform.
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neuraxial dysraphism in epas1 associated syndrome due to improper mesenchymal transition
Neurology Genetics, 2020Co-Authors: Jared S Rosenblum, Ying Pang, Anthony J Cappadona, Davis P Argersinger, Herui Wang, Matthew A Nazari, Jeeva Munasinghe, Danielle R Donahue, Abhishek Jha, James G SmirniotopoulosAbstract:Objective To investigate the effect of somatic, postzygotic, Gain-of-Function Mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in EPAS1 Gain-of-Function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia. Methods Patients referred to our institution for evaluation of new, recurrent, and/or metastatic paragangliomas/pheochromocytoma were confirmed for EPAS1 Gain-of-Function syndrome by identification of the EPAS1 Gain-of-Function Mutation in resected tumors and/or circulating leukocytes. The posterior fossa, its contents, and the spine were evaluated retrospectively on available MRI and CT images of the head and neck performed for tumor staging and restaging. The transgenic mouse model underwent Microfil vascular perfusion and subsequent intact ex vivo 14T MRI and micro-CT as well as gross dissection, histology, and immunohistochemistry to assess the role of EPAS1 in identified malformations. Results All 8 patients with EPAS1 Gain-of-Function syndrome demonstrated incidental posterior fossa malformations—one Dandy-Walker variant and 7 Chiari malformations without syringomyelia. These findings were not associated with a small posterior fossa; rather, the posterior fossa volume exceeded that of its neural contents. Seven of 8 patients demonstrated spinal dysraphism; 4 of 8 demonstrated abnormal vertebral segmentation. The mouse model similarly demonstrated features of neuraxial dysraphism, including cervical myelomeningocele and spinal dysraphism, and cerebellar tonsil displacement through the foramen magnum. Histology and immunohistochemistry demonstrated incomplete mesenchymal transition in the mutant but not the control mouse. Conclusions This study characterized posterior fossa and spinal malformations seen in EPAS1 Gain-of-Function syndrome and suggests that Gain-of-Function Mutation in HIF-2α results in improper mesenchymal transition.
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vascular changes in the retina and choroid of patients with epas1 gain of function Mutation syndrome
JAMA Ophthalmology, 2020Co-Authors: Pauline Dmitriev, Jared S Rosenblum, Herui Wang, Jing Cui, Tamara Prodanov, Alberto S Pappo, Mark R Gilbert, Gerard A Lutty, Chichao Chan, Emily Y ChewAbstract:Importance Patients with theEPAS1Gain-of-Function Mutation syndrome (or Pacak-Zhuang syndrome) present with multiple paragangliomas or pheochromocytomas, duodenal somatostatinoma, polycythemia, headaches, and sometimes diminished visual acuity at an early age. The characteristic phenotype and known genetic cause of the syndrome provide an opportunity to study the role of hypoxia-inducible factor 2α (HIF-2α) in oxygen sensing, development in regions of physiologic hypoxia, and other pathological processes. Objectives To describe the ocular lesions inEPAS1Gain-of-Function Mutation syndrome and to establish whether early-onset diminished visual acuity is developmental or associated with long-term physiologic sequelae of the syndrome. Design, Setting, and Participants This clinical case series with a transgenic murine model study was conducted from July 2013 to June 2019. Participants were 3 patients referred by their primary care physicians to the National Institutes of Health for evaluation of recurrent and metastatic paragangliomas or pheochromocytomas accompanied by polycythemia. The syndrome and somatic mosaicism in patients were confirmed by the identification of Gain-of-Function Mutations in theEPAS1gene in resected tumors and other tissues. Main Outcomes and Measures Ocular findings in patients withEPAS1Gain-of-Function Mutation syndrome. Results A total of 3 patients (mean [SD] age, 29 [6.2] years) with confirmed ocular abnormalities were included in the study. Increased contrast accumulation at the posterior aspect of the globe was seen bilaterally on magnetic resonance imaging scans in all patients. Ophthalmoscopy images demonstrated fibrosis overlying the optic disc, tortuous and dilated retinal vessels, and retinal pigment epithelium changes. Optic disc edema and retinal exudates were also seen. Fluorescein angiography images showed leakage of dye from postcapillary venules surrounding the optic disc and highlighted aberrant retinal vascular patterns. Enhanced-depth imaging optical coherence tomography images showed substantial thickening of the choroid and dilation of choroidal vessels. The ocular features of the syndrome were confirmed with a transgenic model of mice with Gain-of-FunctionEpas1A529VMutation. Conclusions and Relevance In this case series, HIF-2α and hypoxia signaling was found to have a role in vessel development within the choroid and retina, indicating that the marked permanent choroidal thickening and tortuous and dilated veins seen in the choroid and retina in patients withEPAS1Gain-of-Function Mutation syndrome were suggestive of the persistence of venous elements within the developing mesenchyme. These findings may explain other eye and vascular abnormalities whose pathogenesis remains unclear.
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chiari malformation type 1 in epas1 associated syndrome
International Journal of Molecular Sciences, 2019Co-Authors: Jared S Rosenblum, Zhengping Zhuang, Dominic Maggio, Ying Pang, Matthew Nazari, Melissa K Gonzales, Ronald M Lechan, James G Smirniotopoulos, Karel PacakAbstract:A syndrome of multiple paragangliomas/pheochromocytomas, somatostatinoma, and polycythemia due to somatic mosaic Gain-of-Function Mutation of EPAS1, encoding HIF-2α, was previously described. HIF-2α has been implicated in endochondral and intramembranous ossification. Abnormal bone growth of the skull base may lead to Chiari malformation type I. We report two cases of EPAS1 Gain-of-Function Mutation syndrome with Chiari malformation and developmental skull base anomalies. Patients were referred to the Section on Medical Endocrinology, Eunice Kennedy Shriver NICHD, NIH for evaluation of recurrent and metastatic paragangliomas or pheochromocytoma. The syndrome was confirmed genetically by identification of the functional EPAS1 Gain-of-Function Mutation in the resected tumors and circulating leukocytes. Both patients were confirmed for characteristics of EPAS1 Gain-of-Function Mutation syndrome by complete blood count (CBC), plasma biochemistry, and computed tomography (CT) of the abdomen and pelvis. Chiari malformation type I and abnormal bony development of the posterior fossa was found on MRI and CT of the head. The present study implicates EPAS1 Mutations in abnormal posterior fossa development resulting in Chiari malformation type I.
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a transgenic mouse model of pacak zhuang syndrome with an epas1 gain of function Mutation
Cancers, 2019Co-Authors: Herui Wang, Jared S Rosenblum, Ying Pang, Jing Cui, Chunzhang Yang, Qi Zhang, Qi Song, Francia Fang, Mitchell Sun, Pauline DmitrievAbstract:We previously identified a novel syndrome in patients characterized by paraganglioma, somatostatinoma, and polycythemia. In these patients, polycythemia occurs long before any tumor develops, and tumor removal only partially corrects polycythemia, with recurrence occurring shortly after surgery. Genetic mosaicism of Gain-of-Function Mutations of the EPAS1 gene (encoding HIF2α) located in the oxygen degradation domain (ODD), typically p.530–532, was shown as the etiology of this syndrome. The aim of the present investigation was to demonstrate that these Mutations are necessary and sufficient for the development of the symptoms. We developed transgenic mice with a Gain-of-Function Epas1A529V Mutation (corresponding to human EPAS1A530V), which demonstrated elevated levels of erythropoietin and polycythemia, a decreased urinary metanephrine-to-normetanephrine ratio, and increased expression of somatostatin in the ampullary region of duodenum. Further, inhibition of HIF2α with its specific inhibitor PT2385 significantly reduced erythropoietin levels in the mutant mice. However, polycythemia persisted after PT2385 treatment, suggesting an alternative erythropoietin-independent mechanism of polycythemia. These findings demonstrate the vital roles of EPAS1 Mutations in the syndrome development and the great potential of the Epas1A529V animal model for further pathogenesis and therapeutics studies.
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A Transgenic Mouse Model of Pacak–Zhuang Syndrome with An Epas1 Gain-of-Function Mutation
MDPI AG, 2019Co-Authors: Herui Wang, Jared S Rosenblum, Ying Pang, Jing Cui, Chunzhang Yang, Qi Zhang, Qi Song, Francia Fang, Mitchell Sun, Pauline DmitrievAbstract:We previously identified a novel syndrome in patients characterized by paraganglioma, somatostatinoma, and polycythemia. In these patients, polycythemia occurs long before any tumor develops, and tumor removal only partially corrects polycythemia, with recurrence occurring shortly after surgery. Genetic mosaicism of Gain-of-Function Mutations of the EPAS1 gene (encoding HIF2α) located in the oxygen degradation domain (ODD), typically p.530–532, was shown as the etiology of this syndrome. The aim of the present investigation was to demonstrate that these Mutations are necessary and sufficient for the development of the symptoms. We developed transgenic mice with a Gain-of-Function Epas1A529V Mutation (corresponding to human EPAS1A530V), which demonstrated elevated levels of erythropoietin and polycythemia, a decreased urinary metanephrine-to-normetanephrine ratio, and increased expression of somatostatin in the ampullary region of duodenum. Further, inhibition of HIF2α with its specific inhibitor PT2385 significantly reduced erythropoietin levels in the mutant mice. However, polycythemia persisted after PT2385 treatment, suggesting an alternative erythropoietin-independent mechanism of polycythemia. These findings demonstrate the vital roles of EPAS1 Mutations in the syndrome development and the great potential of the Epas1A529V animal model for further pathogenesis and therapeutics studies
Fabio Luiz Fernandesrosa - One of the best experts on this subject based on the ideXlab platform.
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a gain of function Mutation in the clcn2 chloride channel gene causes primary aldosteronism
Nature Genetics, 2018Co-Authors: Ian J. Orozco, Fabio Luiz Fernandesrosa, Georgios Daniil, Corinna Goppner, Rami El M Zein, Vandana Jain, Sheerazed BoulkrounAbstract:Primary aldosteronism is the most common and curable form of secondary arterial hypertension. We performed whole-exome sequencing in patients with early-onset primary aldosteronism and identified a de novo heterozygous c.71G>A/p.Gly24Asp Mutation in the CLCN2 gene, encoding the voltage-gated ClC-2 chloride channel 1 , in a patient diagnosed at 9 years of age. Patch-clamp analysis of glomerulosa cells of mouse adrenal gland slices showed hyperpolarization-activated Cl- currents that were abolished in Clcn2-/- mice. The p.Gly24Asp variant, located in a well-conserved 'inactivation domain'2,3, abolished the voltage- and time-dependent gating of ClC-2 and strongly increased Cl- conductance at resting potentials. Expression of ClC-2Asp24 in adrenocortical cells increased expression of aldosterone synthase and aldosterone production. Our data indicate that CLCN2 Mutations cause primary aldosteronism. They highlight the important role of chloride in aldosterone biosynthesis and identify ClC-2 as the foremost chloride conductor of resting glomerulosa cells.
