Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications

2001 ◽  
Vol 3 (29) ◽  
pp. 1-10 ◽  
Author(s):  
Tahir Tellioglu ◽  
David Robertson
Keyword(s):  
Orthostatic Intolerance ◽  
Clinical Manifestations ◽  
Synaptic Cleft ◽  
Norepinephrine Transporter ◽  
Genetic Mutation ◽  
Clinical Syndrome ◽  
Loss Of Function ◽  
Direct Association ◽  
Type Gene

The norepinephrine transporter (NET) has a major role in terminating the neurochemical signal established by the neurotransmitter norepinephrine (NE) in the synaptic cleft. The NET is also the initial site of action for therapeutic antidepressants, and drugs such as cocaine and amphetamines. Polymorphisms in the NET gene have been identified, and associations with several disorders such as depression have been proposed but not established. However, evidence of a direct association between a genetic mutation of the NET and an autonomic clinical syndrome has recently emerged. A patient and her identical twin were evaluated for typical symptoms of orthostatic intolerance (OI), a disorder mainly characterised by elevated heart rate on standing, and both were found to have clinical and laboratory signs of abnormal uptake of NE. Sequence analysis of the patients' NET gene identified a mutation that resulted in more than 98% loss of function as compared with the wild-type gene. This article reconsiders the important role of the NET protein in the regulation of the nervous and cardiovascular systems, reviews the literature for its polymorphisms and their suggested clinical manifestations, and finally focuses on the effects of its defect on the pathophysiology of OI, the only confirmed direct association between a genetic mutation of the NET and a clinical syndrome.

scholarly journals RIPK1-Associated Inborn Errors of Innate Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahui Zhang ◽  
Taijie Jin ◽  
Ivona Aksentijevich ◽  
Qing Zhou
Keyword(s):  
Immune Deficiency ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Physiological Role ◽  
Model Organisms ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Post Translational Modifications ◽  
Cell Death Signaling

RIPK1 (receptor-interacting serine/threonine-protein kinase 1) is a key molecule for mediating apoptosis, necroptosis, and inflammatory pathways downstream of death receptors (DRs) and pattern recognition receptors (PRRs). RIPK1 functions are regulated by multiple post-translational modifications (PTMs), including ubiquitination, phosphorylation, and the caspase-8-mediated cleavage. Dysregulation of these modifications leads to an immune deficiency or a hyperinflammatory disease in humans. Over the last decades, numerous studies on the RIPK1 function in model organisms have provided insights into the molecular mechanisms of RIPK1 role in the maintenance of immune homeostasis. However, the physiological role of RIPK1 in the regulation of cell survival and cell death signaling in humans remained elusive. Recently, RIPK1 loss-of-function (LoF) mutations and cleavage-deficient mutations have been identified in humans. This review discusses the molecular pathogenesis of RIPK1-deficiency and cleavage-resistant RIPK1 induced autoinflammatory (CRIA) disorders and summarizes the clinical manifestations of respective diseases to help with the identification of new patients.

Hemiplegic Migraine Associated With PRRT2 Mutations: A Clinical and Genetic Study

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012947
Author(s):  
Florence Riant ◽  
Caroline Roos ◽  
Agathe Roubertie ◽  
Cécile Barbance ◽  
Jessica Hadjadj ◽  
...  
Keyword(s):  
Learning Disabilities ◽  
Dominant Gene ◽  
Clinical Manifestations ◽  
Familial Hemiplegic Migraine ◽  
Loss Of Function ◽  
Hemiplegic Migraine ◽  
Pathogenic Variants ◽  
Paroxysmal Kinesigenic Dyskinesia ◽  
Wide Range

Background and objective:PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands.Methods:PRRT2 was analyzed in 860 probands with hemiplegic migraine and PRRT2 mutations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with mutations whose clinical manifestations were detailed.Results:PRRT2 mutations were found in 12 of 163 probands previously tested negative for CACNA1A, ATP1A2 and SCN1A mutations, and in 18 of 697 consecutive probands screened simultaneously on the four genes. In this second group, pathogenic variants were found in 105 subjects, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%) and SCN1A (15%). The PRRT2 mutations included seven distinct variants, five of which already described in persons with paroxysmal kinesigenic dyskinesia, and two new variants. Eight probands had a deletion of the whole PRRT2 gene.Among the 49 PRRT2 mutated patients, 26 had pure hemiplegic migraine, 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4) or abnormal movement (3). Three patients had epilepsy without migraine, two had paroxysmal kinesigenic dyskinesia without migraine, and one was asymptomatic.Conclusion:PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine, and screened in any affected patient, together with the three other main genes. Further studies are needed to understand how the same loss of function PRRT2 mutations can lead to a wide range of neurologic phenotypes including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder and hemiplegic migraine.

scholarly journals Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5927 ◽  
Author(s):  
Zhening Pu ◽  
Haoliang Sun ◽  
Junjie Du ◽  
Yue Cheng ◽  
Keshuai He ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Connective Tissue Disorder ◽  
Pedigree Analysis ◽  
Vital Role ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Whole Exome

Background Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel genetic variants in determining MFS clinical phenotypes. Methods We sequenced the whole exome of 19 individuals derived from three Han Chinese families. The sequencing data were analyzed by a standard pipeline. Variants were further filtered against the public database and an in-house database. Then, we performed pedigree analysis under different inheritance patterns according to American College of Medical Genetics guidelines. Results were confirmed by Sanger sequencing. Results Two novel loss-of-function indels (c.5027_5028insTGTCCTCC, p.D1677Vfs*8; c.5856delG, p.S1953Lfs*27) and one nonsense variant (c.8034C>A, p.Y2678*) of FBN1 were identified in Family 1, Family 2 and Family 3, respectively. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of FBN1 were located in the cbEGF region and a conserved domain across species and were not reported previously. Conclusions Our study extended and strengthened the vital role of FBN1 LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation-based pre- and postnatal screening, genetic diagnosis and clinical management for MFS.

PIK3R1 Mutation Associated with Hyper IgM (APDS2 Syndrome): A Case Report and Review of the Literature

2019 ◽  
Vol 19 (7) ◽  
pp. 941-958
Author(s):  
Reza Yazdani ◽  
Zahra Hamidi ◽  
Fateme Babaha ◽  
Gholamreza Azizi ◽  
Saba Fekrvand ◽  
...  
Keyword(s):  
De Novo ◽  
Hot Spot ◽  
Clinical Manifestations ◽  
Splice Site Mutation ◽  
Genetic Mutation ◽  
Loss Of Function ◽  
Review Of The Literature ◽  
Site Mutation ◽  
Hyper Igm ◽  
Tract Infections

Background and Objective: APDS [Activated phosphoinositide 3-kinase (PI3K) δ Syndrome] is a newly found special form of primary immunodeficiency caused by mutations in genes encoding PI3Kδ subunits and over-activation of the PI3K signaling pathway. Gain-of-function and loss-of-function mutations in PIK3CD (encoding P110δ) and PIK3R1 (encoding p85α, p55α and p50α) lead to APDS1 and APDS2, respectively. The subsequent irregular PI3K downstream signaling cascade is associated with abnormalities in B cells and T cells and the consequent heterogeneous clinical manifestations including respiratory tract infections, autoimmunity, lymphoproliferation and not to mention primary antibody deficiency. In this study, we report a 12-year-old girl with a mutation in the PIK3R1 gene who manifested immunological phenotypes resembling hyper IgM syndrome along with a review of the literature of the previously reported patients. Methods: Whole exome sequencing was performed to detect the underlying genetic mutation in this patient. Results: A de novo heterozygous splice site mutation in the hot spot of the PIK3R1 gene within the intron 10 was found (c.1425+1G>A). Conclusion: Further investigations are required for evaluation of the underlying genetic defects and the possible associations between genetic underpinning and heterogeneous severity and features of the disease.

Modern methods of treating rosacea

2019 ◽  
Vol 1 (7) ◽  
pp. 65-71
Author(s):  
O. A. Egorova ◽  
K. A. Novikov
Keyword(s):  
Clinical Manifestations ◽  
Treatment Method ◽  
Current Data ◽  
Trigger Factors ◽  
Laser Technology ◽  
Individual Approach ◽  
Modern Methods ◽  
Methods Of Treatment ◽  
Choice Of Therapy

Presented current data on the etiology of rosacea, the main aspects of pathogenesis, clinical forms of the disease. Reflects trigger factors leading to rosacea, as well as complicating its course. Modern methods of treatment are described, including the use of new safe preparations of ivermectin and brimonidine, providing a good, lasting effect of clinical manifestations of rosacea. The role of laser technology, actively occupying a leading place in the choice of physiotherapeutic treatment method, is noted. The need for an individual approach in the choice of therapy for each patient with rosacea is emphasized.

The role of adenosinergic system in patients with orthostatic intolerance

2019 ◽  
Author(s):  
Zora Lazurova ◽  
Peter Mitro ◽  
Marta Jakubova ◽  
Milos Simurda ◽  
Eva Durovcova ◽  
...  
Keyword(s):  
Orthostatic Intolerance

Papillon-Lefevre Syndrome: Challenge for Periodontal Management

2019 ◽  
Vol 3 (2) ◽  
pp. 84-86
Author(s):  
Krishna Prasad Lamichhane ◽  
Shaili Pradhan ◽  
Ranjita Shreshta Gorkhali ◽  
Pramod Kumar Koirala
Keyword(s):  
Significant Role ◽  
Autosomal Recessive ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Genetic Mutations ◽  
Rare Autosomal Recessive Disorder ◽  
Diagnosis And Management ◽  
Periodontal Destruction ◽  
Palmoplantar Keratosis

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder associated with rapidly progressing periodontitis leading to premature loss of deciduous and permanent dentition and diffuse palmoplantar keratosis. Immunologic alterations, genetic mutations, and role of bacteria are some aetiologic factors. Patients present with early periodontal destruction, so periodontists play a significant role in diagnosis and management. This paper reports a case of Papillon- Lefevre syndrome with its clinical manifestations and challenges for periodontal management which was diagnosed in dental department.

Disseminated intravascular coagulation syndrome

2020 ◽  
pp. 22-40
Author(s):  
A. Kulikov
Keyword(s):  
Clinical Practice ◽  
Disseminated Intravascular Coagulation ◽  
Blood Cells ◽  
Physical State ◽  
Clinical Manifestations ◽  
Vascular Wall ◽  
Stages Of Development ◽  
Intravascular Coagulation ◽  
Hemostatic Disorder

Presented material reveals main links in the pathogenesis of hemostatic disorder. In particular, attention is paid to the role of the lungs, liver and other organs in the development of this process. Role of vascular wall and blood cells in regulation of the physical state of blood is described in detail. The most frequent factors leading to hypercoagulation are indicated. Difference between hypercoagulation and thrombophilia is shown. The latter is found in clinical practice quite often, but at the same time, it is poorly diagnosed. Such a terrible complication of hemostatic disorder as disseminated intravascular coagulation is described. Its classification, stages of development, clinical manifestations are offered to the readers.

Monogenic Diabetes: Genetics and Relevance on Diabetes Mellitus Personalized Medicine

2020 ◽  
Vol 16 (8) ◽  
pp. 807-819 ◽  
Author(s):  
Madalena Sousa ◽  
Jácome Bruges-Armas
Keyword(s):  
Diabetes Mellitus ◽  
Complex Disease ◽  
Clinical Manifestations ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Diabetes Genetics ◽  
Individualize Treatment

Background: Diabetes mellitus (DM) is a complex disease with significant impression in today's world. Aside from the most common types recognized over the years, such as type 1 diabetes (T1DM) and type 2 diabetes (T2DM), recent studies have emphasized the crucial role of genetics in DM, allowing the distinction of monogenic diabetes. Methods: Authors did a literature search with the purpose of highlighting and clarifying the subtypes of monogenic diabetes, as well as the accredited genetic entities responsible for such phenotypes. Results: The following subtypes were included in this literature review: maturity-onset diabetes of the young (MODY), neonatal diabetes mellitus (NDM) and maternally inherited diabetes and deafness (MIDD). So far, 14 subtypes of MODY have been identified, while three subtypes have been identified in NDM - transient, permanent, and syndromic. Discussion: Despite being estimated to affect approximately 2% of all the T2DM patients in Europe, the exact prevalence of MODY is still unknown, accentuating the need for research focused on biomarkers. Consequently, due to its impact in the course of treatment, follow-up of associated complications, and genetic implications for siblings and offspring of affected individuals, it is imperative to diagnose the monogenic forms of DM accurately. Conclusion: Currently, advances in the genetics field allowed the recognition of new DM subtypes, which until now, were considered slight variations of the typical forms. Thus, it is imperative to act in the close interaction between genetics and clinical manifestations, to facilitate diagnosis and individualize treatment.

The role of microRNA in hepatic ischemia/reperfusion injury

MicroRNA ◽  
2020 ◽  
Vol 09 ◽  
Author(s):  
Chrysanthos D. Christou ◽  
Georgios Tsoulfas
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Clinical Manifestations ◽  
Diagnostic Procedures ◽  
Clinical Tool ◽  
Hepatic Ischemia ◽  
Humoral Factors ◽  
Early Graft ◽  
Hepatic Ischemia Reperfusion

Introduction: Ischemia-reperfusion (I/R) injuries are caused by complex interrelated mechanisms and pathways. Regarding the liver, I/R injuries and their clinical manifestations are crucial for the surgical outcome. Despite its importance, there is no broadly accepted therapy either for the prevention or for the management of I/R injury. I/R injury of the liver can occur either during hepatic surgery (warm) or during the transplantation procedure (cold). MicroRNAs play a pivotal role in the mechanism of I/R injury, as they regulate the expression of the cellular participants and humoral factors associated with I/R injury. Objective: In this review, we highlight the microRNAs that are involved in the I/R injury of the liver, and the molecular pathways that they regulate. In addition, we discuss the potential role of circulating microRNAs as biomarkers and their role as pharmacological targets in the prevention, diagnosis and treatment of I/R injuries. Method: We conducted a comprehensive review of the PubMed bibliographic database regarding microRNAs and I/R injuries of the liver. Results: In diagnostics, microRNA panels could replace invasive diagnostic procedures, relieving patients of the associated complications. In therapeutics, microRNA agomirs, antagomirs and other drugs can be used to shift the balance between proapoptotic and survival pathways, to alleviate the liver damage caused by I/R. In transplantation procedures, microRNA profiling could decrease the incidence of early graft dysfunction, especially regarding marginal grafts. Conclusion: Although microRNAs seem a very promising clinical tool in the management of I/R injuries, further research is required, until microRNAs become a novel tool in the diagnosis and monitoring of an I/R injury of the liver.

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