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BioRxiv : the Preprint Server For... Jun 2023Andersen-Tawil Syndrome Type 1 (ATS1) is a rare heritable disease caused by mutations in the strong inwardly rectifying K channel Kir2.1. The extracellular...
BACKGROUND
Andersen-Tawil Syndrome Type 1 (ATS1) is a rare heritable disease caused by mutations in the strong inwardly rectifying K channel Kir2.1. The extracellular Cys122-to-Cys154 disulfide bond in the Kir2.1 channel structure is crucial for proper folding, but has not been associated with correct channel function at the membrane. We tested whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing the open state of the channel.
METHODS AND RESULTS
We identified a Kir2.1 loss-of-function mutation in Cys122 (c.366 A>T; p.Cys122Tyr) in a family with ATS1. To study the consequences of this mutation on Kir2.1 function we generated a cardiac specific mouse model expressing the Kir2.1 mutation. Kir2.1 animals recapitulated the abnormal ECG features of ATS1, like QT prolongation, conduction defects, and increased arrhythmia susceptibility. Kir2.1 mouse cardiomyocytes showed significantly reduced inward rectifier K (I) and inward Na (I) current densities independently of normal trafficking ability and localization at the sarcolemma and the sarcoplasmic reticulum. Kir2.1 formed heterotetramers with wildtype (WT) subunits. However, molecular dynamic modeling predicted that the Cys122-to-Cys154 disulfide-bond break induced by the C122Y mutation provoked a conformational change over the 2000 ns simulation, characterized by larger loss of the hydrogen bonds between Kir2.1 and phosphatidylinositol-4,5-bisphosphate (PIP) than WT. Therefore, consistent with the inability of Kir2.1 channels to bind directly to PIP in bioluminescence resonance energy transfer experiments, the PIP binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch-clamping the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing PIP concentrations.
CONCLUSION
The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential to channel function. We demonstrated that ATS1 mutations that break disulfide bonds in the extracellular domain disrupt PIP-dependent regulation, leading to channel dysfunction and life-threatening arrhythmias.
PubMed: 37333254
DOI: 10.1101/2023.06.07.544151 -
Sleep Medicine Reviews Jun 2023Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms.... (Meta-Analysis)
Meta-Analysis Review
Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms. However, the nature and magnitude of sleep architecture alteration in ME/CFS is not known, with studies using objective sleep measures in ME/CFS generating contradictory results. The current manuscript aimed to review and meta-analyse of case-control studies with objective sleep measures in ME/CSF. A search was conducted in PubMed, Scopus, Medline, Google Scholar, and Psychoinfo databases. After review, 24 studies were included in the meta-analysis, including 20 studies with 801 adults (ME/CFS = 426; controls = 375), and 4 studies with 477 adolescents (ME/CFS = 242; controls = 235), who underwent objective measurement of sleep. Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, reduced sleep efficiency, decreased stage 2 sleep, more Stage 3, and longer rapid eye movement sleep latency. However, adolescent ME/CFS patients had longer time in bed, longer total sleep time, longer sleep onset latency, and reduced sleep efficiency. The meta-analysis results demonstrate that sleep is altered in ME/CFS, with changes seeming to differ between adolescent and adults, and suggesting sympathetic and parasympathetic nervous system alterations in ME/CFS.
Topics: Adult; Adolescent; Humans; Fatigue Syndrome, Chronic; Sleep; Sleep, REM; Sleep Latency; Sleep Duration
PubMed: 36948138
DOI: 10.1016/j.smrv.2023.101771 -
Ugeskrift For Laeger Nov 2019This review describes congenital anomalies of the external ear, which are common and include a wide range of malformations. Attentiveness to other malformations in... (Review)
Review
This review describes congenital anomalies of the external ear, which are common and include a wide range of malformations. Attentiveness to other malformations in newborns with ear anomalies is important, as they often appear as part of syndromes such as Goldenhar syndrome, Treacher Collins syndrome and branchio-oto-renal syndrome. This review is an overview of the most common congenital anomalies of the external ear and their treatment, including microtia, constricted ears, preauricular pits, tags and prominent ears.
Topics: Branchio-Oto-Renal Syndrome; Ear, External; Humans; Infant, Newborn
PubMed: 31791458
DOI: No ID Found -
Endocrine Connections Feb 2024Endometriosis and polycystic ovary syndrome (PCOS) are common gynecological disorders that constitute a significant burden of disease in women of fertile age. The... (Review)
Review
Endometriosis and polycystic ovary syndrome (PCOS) are common gynecological disorders that constitute a significant burden of disease in women of fertile age. The disorders share a link to female reproduction and infertility; however, divergent effects on menstrual cycle, related hormones, and body composition have been proposed. Disorders of the thyroid gland including abnormal thyroid dysfunction (hyperthyroidism or hypothyroidism) and/or markers of thyroid autoimmunity similarly show a female predominance and onset in younger age groups. We reviewed the literature on the association between endometriosis, PCOS, and thyroid disease up until July 1, 2023, and identified 8 original studies on endometriosis and thyroid disease and 30 original studies on PCOS and thyroid disease. The studies were observational and heterogeneous regarding the design, sample size, and definitions of exposure and outcome; however, a tendency was seen toward an association between hyperthyroidism and endometriosis. Especially an association between endometriosis and slightly elevated levels of thyroid-stimulating hormone receptor antibodies has been found and corroborated in studies from different populations. On the other hand, the literature review turned a focus toward an association between hypothyroidism and PCOS, however, with uncertainties as to whether the association is caused by hypothyroidism per se and/or the thyroid autoantibodies (thyroid peroxidase and thyroglobulin antibodies). More evidence is needed to substantiate an association between endometriosis, PCOS, and thyroid disease, and to differentiate between the role of thyroid function and thyroid autoimmunity. Furthermore, studies are warranted to extend knowledge on the different disease characteristics and underlying mechanisms.
PubMed: 38078917
DOI: 10.1530/EC-23-0431 -
Annals of Medicine 2004Due to its varied and variable phenotypes, Andersen-Tawil syndrome (ATS) holds a unique place in the field of channelopathies. Patients with ATS typically present with... (Review)
Review
Due to its varied and variable phenotypes, Andersen-Tawil syndrome (ATS) holds a unique place in the field of channelopathies. Patients with ATS typically present with the triad of periodic paralysis, cardiac arrhythmias, and developmental dysmorphisms. Although penetrance of ATS is high, disease expression and severity are remarkably variable. Mutations in KCNJ2 are the primary cause of ATS with 21 mutations discovered in 30 families. These mutations affect channel function through heterogeneous mechanisms, including reduced PIP2-related channel activation and altered pore function. Aside from KCNJ2-based ATS, the genetic basis of this disease in nearly 40% of cases is unknown. Other ATS genes likely share a common pathway or function with Kir2.1 or facilitate the activity of this ion channel. In this review, we explore hypotheses explaining the pathogenesis, expression, and variability of ATS.
Topics: Arrhythmias, Cardiac; Genetic Heterogeneity; Humans; Long QT Syndrome; Mutation; Paralysis, Hyperkalemic Periodic; Potassium Channels, Inwardly Rectifying; Syndrome
PubMed: 15176430
DOI: 10.1080/17431380410032490 -
Cureus Aug 2020Periodic paralyses are a group of disorders characterized by episodes of muscle paralyses. They are mainly divided as primary (hereditary) and secondary (acquired)... (Review)
Review
Periodic paralyses are a group of disorders characterized by episodes of muscle paralyses. They are mainly divided as primary (hereditary) and secondary (acquired) periodic paralyses. Primary periodic paralyses occur as a result of mutations in genes encoding subunits of muscle membrane channel proteins such as sodium, calcium, and potassium channels, resulting in impairment of their properties. Primary periodic paralyses are further classified on the basis of affected ion channels and other associated complications. Some of these periodic paralyses are hyperkalemic periodic paralysis (Na-channel mutation), hypokalemic periodic paralysis (Na- or Ca-channel mutation), Andersen's syndrome (K-channel mutation), etc.
PubMed: 33005530
DOI: 10.7759/cureus.10112 -
Circulation. Genomic and Precision... Oct 2018Girls and women with Turner syndrome face a lifelong struggle with both congenital heart disease and acquired cardiovascular conditions. Bicuspid aortic valve is common,... (Review)
Review
Girls and women with Turner syndrome face a lifelong struggle with both congenital heart disease and acquired cardiovascular conditions. Bicuspid aortic valve is common, and many have left-sided heart obstructive disease of varying severity, from hypoplastic left-sided heart syndrome to minimal aortic stenosis or coarctation of the aorta. Significant enlargement of the thoracic aorta may progress to catastrophic aortic dissection and rupture. It is becoming increasingly apparent that a variety of other cardiovascular conditions, including early-onset hypertension, ischemic heart disease, and stroke, are the major factors reducing the life span of those with Turner syndrome. The presentations and management of cardiovascular conditions in Turner syndrome differ significantly from the general population. Therefore, an international working group reviewed the available evidence regarding the diagnosis and treatment of cardiovascular diseases in Turner syndrome. It is recognized that the suggestions for clinical practice stated here are only the beginning of a process that must also involve the establishment of quality indicators, structures and processes for implementation, and outcome studies.
Topics: American Heart Association; Aortic Dissection; Aortic Coarctation; Aortic Valve; Bicuspid Aortic Valve Disease; Female; Heart Defects, Congenital; Heart Valve Diseases; Humans; Hypertension; Turner Syndrome; United States
PubMed: 30354301
DOI: 10.1161/HCG.0000000000000048 -
Frontiers in Endocrinology 2023Skeletal stem/progenitor cells (SSPCs) in the bone marrow can differentiate into osteoblasts or adipocytes in response to microenvironmental signalling input, including...
BACKGROUND
Skeletal stem/progenitor cells (SSPCs) in the bone marrow can differentiate into osteoblasts or adipocytes in response to microenvironmental signalling input, including hormonal signalling. Glucocorticoids (GC) are corticosteroid hormones that promote adipogenic differentiation and are endogenously increased in patients with Cushing´s syndrome (CS). Here, we investigate bone marrow adiposity changes in response to endogenous or exogenous GC increases. For that, we characterize bone biopsies from patients with CS and post-menopausal women with glucocorticoid-induced osteoporosis (GC-O), compared to age-matched controls, including postmenopausal osteoporotic patients (PM-O).
METHODS
Transiliac crest bone biopsies from CS patients and healthy controls, and from postmenopausal women with GC-O and matched controls were analysed; an additional cohort included biopsies from women with PM-O. Plastic-embedded biopsies were sectioned for histomorphometric characterization and quantification of adipocytes. The fraction of adipocyte area per tissue (Ad.Ar/T.Ar) and marrow area (Ad.Ar/Ma.Ar), mean adipocyte profile area (Ad.Pf.Ar) and adipocyte profile density (N.Ad.Pf/Ma.Ar) were determined and correlated to steroid levels. Furthermore, the spatial distribution of adipocytes in relation to trabecular bone was characterized and correlations between bone marrow adiposity and bone remodeling parameters investigated.
RESULTS
Biopsies from patients with CS and GC-O presented increased Ad.Ar/Ma.Ar, along with adipocyte hypertrophy and hyperplasia. In patients with CS, both Ad.Ar/Ma.Ar and Ad.Pf.Ar significantly correlated with serum cortisol levels. Spatial distribution analyses revealed that, in CS, the increase in Ad.Ar/Ma.Ar near to trabecular bone (<100 µm) was mediated by both adipocyte hypertrophy and hyperplasia, while N.Ad.Pf/Ma.Ar further into the marrow (>100 µm) remained unchanged. In contrast, patients with GC-O only presented increased Ad.Ar/Ma.Ar and mean Ad.Pf.Ar>100 µm from trabecular bone surface, highlighting the differential effect of increased endogenous steroid accumulation. Finally, the Ad.Ar/Ma.Ar and Ad.Ar/T.Ar correlated with the canopy coverage above remodeling events.
CONCLUSION
Increased cortisol production in patients with CS induces increased bone marrow adiposity, primarily mediated by adipocyte hypertrophy. This adiposity is particularly evident near trabecular bone surfaces, where hyperplasia also occurs. The differential pattern of adiposity in patients with CS and GC-O highlights that bone marrow adipocytes and their progenitors may respond differently in these two GC-mediated bone diseases.
Topics: Humans; Female; Bone Marrow; Glucocorticoids; Cushing Syndrome; Adiposity; Postmenopause; Hyperplasia; Hydrocortisone; Osteoporosis, Postmenopausal; Osteoporosis; Hypertrophy
PubMed: 37881495
DOI: 10.3389/fendo.2023.1232574 -
Journal of Cardiology Nov 2017Andersen-Tawil syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5. It is characterized by arrhythmias, neurological symptoms, and...
BACKGROUND
Andersen-Tawil syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5. It is characterized by arrhythmias, neurological symptoms, and dysmorphic features. The present study retrospectively examined the characteristics of 11 unrelated families with ATS.
METHODS
This study consisted of 11 probands positive for KCNJ2 variants and 33 family members (mean age 30.0±17.3 years, female n=31). Additional genetic screening of 3 LQTS genes (KCNQ1, KCNH2, SCN5A) was performed in 9 families. Predictors of arrhythmias [premature ventricular beats>2000/24h, biventricular and polymorphic ventricular tachycardia (VT)], syncope, and/or cardiac arrest (CA) were evaluated.
RESULTS
In KCNJ2 mutation carriers vs non-carriers (n=25 vs n=19) significant differences were observed in U-wave manifestations in V2-V4, T-T duration, QTUc duration (p<0.0001), dysmorphic features, and neurological symptoms. Compared to asymptomatic carriers (n=9), in those with arrhythmias and/or syncope and/or CA (n=16) micrognathia (p=0.004), periodic paralysis (p=0.019), palpitation (p=0.005), U-wave n V2-V4 (p=0.049) were more frequent; QTU (p=0.045) and T-T (p=0.014) were also longer (n=9). In the subgroup of carriers with syncope and/or cardiac arrest (n=10, 90% women), K897T-KCNH2 polymorphism (p=0.02), periodic paralysis (p=0.004), muscle weakness (p=0.04), palpitations (p=0.04), arrhythmias (biventricular VT, p=0.003; polymorphic VT, p=0.009) were observed more frequently. T-T duration was longer (p=0.007) and the percentage of patients with premature ventricular contraction >2000/24h was higher (p=0.005).
CONCLUSION
A higher risk of arrhythmia, syncope, and/or CA is associated with the presence of micrognathia, periodic paralysis, and prolonged T-T time. Our findings suggest that K897T may contribute to the occurrence of syncope.
Topics: Adolescent; Adult; Andersen Syndrome; Child; Child, Preschool; ERG1 Potassium Channel; Female; Genetic Testing; Heart Arrest; Humans; Male; Micrognathism; Middle Aged; NAV1.5 Voltage-Gated Sodium Channel; Polymorphism, Genetic; Syncope; Tachycardia, Ventricular; Ventricular Premature Complexes; Young Adult
PubMed: 28336205
DOI: 10.1016/j.jjcc.2017.01.009 -
Frontiers in Immunology 2018Peptides vaccination is an interesting approach to activate T-cells toward desired antigens in hematological malignancies. In addition to classical tumor associated... (Review)
Review
Peptides vaccination is an interesting approach to activate T-cells toward desired antigens in hematological malignancies. In addition to classical tumor associated antigens, such as cancer testis antigens, new potential targets for peptide vaccination comprise neo-antigens including JAK2 and CALR mutations, and antigens from immune regulatory proteins in the tumor microenvironment such as programmed death 1 ligands (PD-L1 and PD-L2). Immunosuppressive defenses of tumors are an important challenge to overcome and the T cell suppressive ligands PD-L1 and PD-L2 are often present in tumor microenvironments. Thus, PD-L1 and PD-L2 are interesting targets for peptide vaccines in diseases where the tumor microenvironment is known to play an essential role such as multiple myeloma and follicular lymphoma. In myelodysplastic syndromes the drug azacitidine re-exposes tumor associated antigens, why vaccination with related peptides would be an interesting addition. In myeloproliferative neoplasms the JAK2 and CALR mutations has proven to be immunogenic neo-antigens and thus possible targets for peptide vaccination. In this mini review we summarize the basis for these novel approaches, which has led to the initiation of clinical trials with various peptide vaccines in myelodysplastic syndromes, myeloproliferative neoplasms, multiple myeloma, and follicular lymphoma.
Topics: Antigens, Neoplasm; B7-H1 Antigen; Cancer Vaccines; Hematologic Neoplasms; Humans; Lymphoma, Follicular; Molecular Targeted Therapy; Programmed Cell Death 1 Ligand 2 Protein; Tumor Microenvironment; Vaccines, Subunit
PubMed: 30327655
DOI: 10.3389/fimmu.2018.02264