Clinical case of type I interferonopathy: homozygous STAT2 gain-of-function mutation

2021 ◽  
Vol 20 (3) ◽  
pp. 132-139
Author(s):  
А. L. Kozlova ◽  
М. Е. Leonteva ◽  
V. I. Burlakov ◽  
Z. А. Nesterenko ◽  
О. М. Laba ◽  
...  
Keyword(s):  
Side Effects ◽  
Clinical Case ◽  
Kinase Inhibitor ◽  
Genetic Defect ◽  
Type I ◽  
Gain Of Function ◽  
The World ◽  
Key Aspects ◽  
Methods Of Treatment ◽  
Type I Interferonopathies

The article is devoted to an extremely rare variant of type I interferonopathies associated with a homozygous gain of function (GOF) mutation in the STAT2 gene in a 5-year-old child. This genetic defect was first described in 2019, and so far only 3 cases are known in the world with a similar pathology. Here we present the fourth clinical case and our experience in managing a patient with STAT2 GOF. The article presents the key aspects of the pathogenesis, clinical picture based on the analysis of all known cases of the disease. The absence of established criteria and methods of treatment for this disease is due to the rarity and relative novelty of the described nosology. We present the experience of treatment using a JAK kinase inhibitor, followed by an assessment of the effectiveness of the therapy and side effects. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

scholarly journals Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

2019 ◽  
Author(s):  
Conor Gruber ◽  
Marta Martin-Fernandez ◽  
Fatima Ailal ◽  
Xueer Qiu ◽  
Justin Taft ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Transcriptional Activity ◽  
Type I Interferon ◽  
Early Response ◽  
Type I ◽  
Homozygous State ◽  
Gain Of Function ◽  
Monogenic Disorders ◽  
Sterically Hinder ◽  
Type I Interferonopathies

AbstractType I interferonopathies are monogenic disorders characterized by enhanced Type I interferon (IFN-I) activity. Inherited ISG15 and USP18 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, ISG15/USP18 are induced by IFN-I and sterically hinder JAK1 from binding to the IFNAR2 subunit of IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is gain-of-function (GOF) for ISGF3-dependent induction of late but not early response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic transcriptional activity of ISGF3. Rather, the STAT2 R148Q variant is GOF because it fails to appropriately interact with and traffic USP18 to IFNAR2, preventing USP18 from negatively regulating responses to IFN-I. Overall, a STAT2 missense mutation that fails to facilitate USP18-mediated signal termination in the homozygous state underlies a novel genetic etiology of type I interferonopathy.

scholarly journals Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

2020 ◽  
Vol 217 (5) ◽  
Author(s):  
Conor Gruber ◽  
Marta Martin-Fernandez ◽  
Fatima Ailal ◽  
Xueer Qiu ◽  
Justin Taft ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Type I Interferon ◽  
Cellular Responses ◽  
Early Response ◽  
Intrinsic Activity ◽  
Type I ◽  
Gain Of Function ◽  
Monogenic Disorders ◽  
Transcriptional Complex ◽  
Type I Interferonopathies

Type I interferonopathies are monogenic disorders characterized by enhanced type I interferon (IFN-I) cytokine activity. Inherited USP18 and ISG15 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, USP18, being stabilized by ISG15, sterically hinders JAK1 from binding to the IFNAR2 subunit of the IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is a gain of function (GOF) for induction of the late, but not early, response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic activity of the STAT2-containing transcriptional complex responsible for IFN-I–stimulated gene induction. Rather, the STAT2 R148Q variant is a GOF because it fails to appropriately traffic USP18 to IFNAR2, thereby preventing USP18 from negatively regulating responses to IFN-I. Homozygosity for STAT2 R148Q represents a novel molecular and clinical phenocopy of inherited USP18 deficiency, which, together with inherited ISG15 deficiency, defines a group of type I interferonopathies characterized by an impaired regulation of late cellular responses to IFN-I.

The Genetic Defect of Type I von Willebrand Disease “Vicenza” Is Linked to the von Willebrand Factor Gene

1993 ◽  
Vol 69 (02) ◽  
pp. 173-176 ◽  
Author(s):  
Anna M Randi ◽  
Elisabetta Sacchi ◽  
Gian Carlo Castaman ◽  
Francesco Rodeghiero ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Von Willebrand Factor ◽  
Autosomal Dominant ◽  
Genetic Defect ◽  
Von Willebrand Disease ◽  
Type I ◽  
Bleeding Tendency ◽  
Factor Gene ◽  
Low Levels ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryType I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF contrasting with a mild bleeding tendency. The pathophysiology of this subtype is still unknown. The presence of supranormal multimers in the patients’ plasma could be due to a mutation in the vWF molecule which affects post-translational processing, or to a defect in the cells’ processing machinery, independent of the vWF molecule. In order to determne if type I vWD Vicenza is linked to the vWF gene, we studied six polymorphic systems identified within the vWF gene in two apparently unrelated families with type I vWD Vicenza. The results of this study indicate a linkage between vWF gene and the type I vWD Vicenza trait. This strongly suggests that type I vWD Vicenza is due to a mutation in one of the vWF alleles, which results in an abnormal vWF molecule that is processed to a lesser extent than normal vWF.

Abnormal Processing of the Glycoprotein IIb Transcript due to a Nonsense Mutation in Exon 17 Associated with Glanzmann’s Thrombasthenia

1995 ◽  
Vol 73 (05) ◽  
pp. 756-762 ◽  
Author(s):  
Yoshiaki Tomiyama ◽  
Hirokazu Kashiwagi ◽  
Satoru Kosugi ◽  
Masamichi Shiraga ◽  
Yoshio Kanayama ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Molecular Genetic ◽  
Genetic Defect ◽  
Nucleotide Sequence Analysis ◽  
Type I ◽  
Normal Amount ◽  
Immunoblot Assay ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia ◽  
Pcr Products

SummaryWe analyzed the molecular genetic defect responsible for type I Glanzmann’s thrombasthenia in a Japanese patient. In an immunoblot assay using polyclonal anti-GPIIb-IIIa antibodies, some GPIIIa (15% of normal amount) could be detected in the patient’s platelets, whereas GPIIb could not (<2% of normal amount). Nucleotide sequence analysis of platelet GPIIb mRNA-derived polymerase chain reaction (PCR) products revealed that patient’s GPIIb cDNA had a 75-bp deletion in the 3’ boundary of exon 17 resulting in an in-frame deletion of 25 amino acids. DNA analysis and family study revealed that the patient was a compound heterozygote of two GPIIb gene defects. One allele derived from her father was not expressed in platelets, and the other allele derived from her mother had a 9644C → T mutation which was located at the position -3 of the splice donor junction of exon 17 and resulted in a termination codon (TGA). Moreover, quantitative analysis demonstrated that the amount of the abnormal GPIIb transcript in the patient’s platelets was markedly reduced. Thus, the C → T mutation resulting in the abnormal splicing of GPIIb transcript and the reduction in its amount is responsible for Glanzmann’s thrombasthenia.

Antidiabetic effect of Psychotria malayana Jack in induced type 1 diabetic rat

MEDISAINS ◽  
2020 ◽  
Vol 18 (1) ◽  
pp. 19
Author(s):  
Fairuz Fairuz ◽  
Hasna Dewi ◽  
Humaryanto Humaryanto
Keyword(s):  
Blood Glucose ◽  
Side Effects ◽  
Type I Diabetes ◽  
Langerhans Cell ◽  
Diabetic Rat ◽  
Type I ◽  
Antidiabetic Effect ◽  
Glucose Levels ◽  
Blood Glucose Levels

Background: Therapies for hyperglycemic treatment, including insulin and oral diabetes medications, have been confirmed to cause several side effects. Thus, finding new drugs with fewer side effects is of high importance. Salung leaf herb (Psychotria malayana Jack) reported used in traditional societies as a treatment for diabetes. However, the scientific proof of this plant for diabetes treatment is still lacking.Objective: To evaluate the antidiabetic effect of the P. malayana jack in induced type 1 diabetic rats by assessing blood glucose level and pancreatic cells in white rats.Methods: Alloxan used to induce type I diabetes. Rats randomly divided into six groups. A Group P1 received 250 mg/kg BW; group P2 received 500 mg/kg BW, group P3 received 1000 mg/kg BW. While group 4 basal received no treatment, group 5 received distilled water as a negative control, and group 6 received glibenclamide as a positive control. Medications are given for six days. Glucose levels were measured, and observation of pancreatic Langerhans cell damages.Results:  A decrease in blood glucose levels observed in all treatment groups. The most significant reduction (49.76%; 1000 mg/kg BW) occurred in the P3 group. Morphological features of pancreatic Langerhans cell damage were slightly high in the P1 group.Conclusion: P. malayana Jack can consider having an antidiabetic effect in a type 1 diabetic rat by reducing blood glucose levels.

KEY ASPECTS OF TRANSFORMATION OF THE STATE AUTHORITIES IN THE WORLD AND TO THE MODERN SOVERUM UKRAINE: A JOINT AND PERSONALITY

2018 ◽  
Vol 1 (11) ◽  
pp. 164-174
Author(s):  
Оlena Fedorіvna Caracasidi
Keyword(s):  
Separation Of Powers ◽  
Human Life ◽  
State Power ◽  
The State ◽  
Public Power ◽  
The People ◽  
Large Numbers ◽  
The World ◽  
Distribution Of Power ◽  
Key Aspects

The article deals with the fundamental, inherent in most of the countries of the world transformation of state power, its formation, functioning and division between the main branches as a result of the decentralization of such power, its subsidiarity. Attention is drawn to the specifics of state power, its func- tional features in the conditions of sovereignty of the states, their interconnec- tion. It is emphasized that the nature of the state power is connected with the nature of the political system of the state, with the form of government and many other aspects of a fundamental nature.It is analyzed that in the middle of national states the questions of legitima- cy, sovereignty of transparency of state power, its formation are acutely raised. Concerning the practical functioning of state power, a deeper study now needs a problem of separation of powers and the distribution of power. The use of this principle, which ensures the real subsidiarity of the authorities, the formation of more effective, responsible democratic relations between state power and civil society, is the first priority of the transformation of state power in the conditions of modern transformations of countries and societies. It is substantiated that the research of these problems will open up much wider opportunities for the provi- sion of state power not as a center authority, but also as a leading political structure but as a power of the people and the community. In the context of global democratization processes, such processes are crucial for a more humanistic and civilized arrangement of human life. It is noted that local self-government, as a specific form of public power, is also characterized by an expressive feature of a special subject of power (territorial community) as a set of large numbers of people; joint communal property; tax system, etc.

Experimental Measurement of Turbulent Diffusion, Initial Dilution and T90

1986 ◽  
Vol 18 (11) ◽  
pp. 131-140
Author(s):  
Edmundo Garcia Agudo ◽  
Jose Leomax dos Santos
Keyword(s):  
Experimental Measurement ◽  
Tracer Technique ◽  
Initial Dilution ◽  
Coastal Cities ◽  
Actual Solution ◽  
The World ◽  
Visual Aid ◽  
Proper Design ◽  
Key Aspects ◽  
Bacterial Concentrations

The final disposal of sewage using submarine outfalls has become an actual solution for coastal cities all over the world. In order to get the best results it is necessary to carry out specific studies for the proper design of the outfall. Dilution and decrease in bacterial concentrations are two key aspects for the design. Radioisotope tracers have been used extensively in studies performed in some Brazilian waterbodies where outfall systems exist or are to be installed. As far as dilution measurement is concerned, both point and continuous radiotracer injections can provide useful results. The T90 measurements can be better accomplished using a combined tracer technique for sampling the sewage field, using the radiotracer for dilution measurement and rhodamine B as a visual aid. Typical results of dilution measurement using both techniques mentioned, as well as a summary of T 90 results obtained for the Santos, Fortaleza and Maceió outfalls are presented.

Encapsulation of Imatinib in Targeted KIT-5 Nanoparticles for Reducing its Cardiotoxicity and Hepatotoxicity

2020 ◽  
Vol 20 (16) ◽  
pp. 1966-1980
Author(s):  
Jaleh Varshosaz ◽  
Saeedeh Fardshouraki ◽  
Mina Mirian ◽  
Leila Safaeian ◽  
Setareh Jandaghian ◽  
...  
Keyword(s):  
Controlled Release ◽  
Side Effects ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Drug Carrier ◽  
Free Drug ◽  
Jurkat Cells ◽  
Targeted Nanoparticles ◽  
Inhibitor Drug ◽  
Histopathological Results

Background: Using imatinib, a tyrosine kinase inhibitor drug used in lymphoblastic leukemia, has always had limitations due to its cardiotoxicity and hepatotoxicity side effects. The objective of this study is to develop a target-oriented drug carrier to minimize these adverse effects by the controlled release of the drug. Methods: KIT-5 nanoparticles were functionalized with 3-aminopropyltriethoxysilane and conjugated to rituximab as the targeting agent for the CD20 positive receptors of the B-cells. Then they were loaded with imatinib and their physical properties were characterized. The cell cytotoxicity of the nanoparticles was studied by MTT assay in Ramos (CD20 positive) and Jurkat cell lines (CD20 negative) and their cellular uptake was shown by fluorescence microscope. Wistar rats received an intraperitoneal injection of 50 mg/kg of the free drug or targeted nanoparticles for 21 days. Then the level of aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH) were measured in serum of animals. The cardiotoxicity and hepatotoxicity of the drug were also studied by hematoxylin and eosin staining of the tissues. Results: The targeted nanoparticles of imatinib showed to be more cytotoxic to Ramos cells rather than Jurkat cells. The results of the biochemical analysis displayed a significant reduction in AST, ALT, ALP, and LDH levels in animals treated with targeted nanoparticles, compared to the free drug group. By comparison with the free imatinib, histopathological results represented less cardiotoxicity and hepatotoxicity in the animals, which received the drug through the current designed delivery system. Conclusion: The obtained results confirmed that the rituximab targeted KIT-5 nanoparticles are promising in the controlled release of imatinib and could decrease its cardiotoxicity and hepatotoxicity side effects.

Remaking Retirement

2020 ◽  
Keyword(s):  
Interest Rates ◽  
Older Workers ◽  
Older Persons ◽  
The United States ◽  
Older Population ◽  
The Past ◽  
Cost Of Education ◽  
The World ◽  
Low Interest Rates ◽  
Key Aspects

Around the world, people nearing and entering retirement are holding ever-greater levels of debt than in the past. This is not a benign situation, as many pre-retirees and retirees are stressed about their indebtedness. Moreover, this growth in debt among the older population may render retirees vulnerable to financial shocks, medical care bills, and changes in interest rates. Contributors to this volume explore key aspects of the rise in debt across older cohorts, drill down into the types of debt and reasons for debt incurred by the older population, and review policies to remedy some of the financial problems facing older persons, in the United States and elsewhere. The authors explore which groups are most affected by debt, and they also identify the factors causing this important increase in leverage at older ages. It is clear that the economic and market environments are influential when it comes to saving and debt. Access to easy borrowing, low interest rates, and the rising cost of education have had important impacts on how much people borrow, and how much debt they carry at older ages. In this environment, the capacity to manage debt is ever more important as older workers lack the opportunity to recover for mistakes.

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