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2.
Philos Trans R Soc Lond B Biol Sci ; 378(1879): 20220164, 2023 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-37122208

RESUMO

Influx of sodium ions through voltage-gated sodium channels in cardiomyocytes is essential for proper electrical conduction within the heart. Both acquired conditions associated with sodium channel dysfunction (myocardial ischaemia, heart failure) as well as inherited disorders secondary to mutations in the gene SCN5A encoding for the cardiac sodium channel Nav1.5 are associated with life-threatening arrhythmias. Research in the last decade has uncovered the complex nature of Nav1.5 distribution, function, in particular within distinct subcellular subdomains of cardiomyocytes. Nav1.5-based channels furthermore display previously unrecognized non-electrogenic actions and may impact on cardiac structural integrity, leading to cardiomyopathy. Moreover, SCN5A and Nav1.5 are expressed in cell types other than cardiomyocytes as well as various extracardiac tissues, where their functional role in, e.g. epilepsy, gastrointestinal motility, cancer and the innate immune response is increasingly investigated and recognized. This review provides an overview of these novel insights and how they deepen our mechanistic knowledge on SCN5A channelopathies and Nav1.5 (dys)function. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.


Assuntos
Cardiomiopatias , Canalopatias , Epilepsia , Humanos , Canalopatias/genética , Canalopatias/metabolismo , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Mutação , Cardiomiopatias/genética , Epilepsia/genética
3.
Handb Exp Pharmacol ; 279: 3-39, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36592225

RESUMO

In skeletal muscle, excitation-contraction (EC) coupling relies on the mechanical coupling between two ion channels: the L-type voltage-gated calcium channel (CaV1.1), located in the sarcolemma and functioning as the voltage sensor of EC coupling, and the ryanodine receptor 1 (RyR1), located on the sarcoplasmic reticulum serving as the calcium release channel. To this day, the molecular mechanism by which these two ion channels are linked remains elusive. However, recently, skeletal muscle EC coupling could be reconstituted in heterologous cells, revealing that only four proteins are essential for this process: CaV1.1, RyR1, and the cytosolic proteins CaVß1a and STAC3. Due to the crucial role of these proteins in skeletal muscle EC coupling, any mutation that affects any one of these proteins can have devastating consequences, resulting in congenital myopathies and other pathologies.Here, we summarize the current knowledge concerning these four essential proteins and discuss the pathophysiology of the CaV1.1, RyR1, and STAC3-related skeletal muscle diseases with an emphasis on the molecular mechanisms. Being part of the same signalosome, mutations in different proteins often result in congenital myopathies with similar symptoms or even in the same disease.


Assuntos
Canalopatias , Doenças Musculares , Humanos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Canalopatias/genética , Proteínas Adaptadoras de Transdução de Sinal , Acoplamento Excitação-Contração/fisiologia , Músculo Esquelético/fisiologia , Doenças Musculares/genética , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio
4.
Biochim Biophys Acta Biomembr ; 1865(2): 184085, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36403799

RESUMO

TRPV4 is a polymodal and non-selective cation channel that is activated by multiple physical and chemical stimuli. >50 naturally occurring point-mutation of TRPV4 have been identified in human, most of which induce different diseases commonly termed as channelopathies. While, these mutations are either "gain-of-function" or "loss-of-function" in nature, the exact molecular and cellular mechanisms behind such diverse channelopathies are largely unknown. In this work, we analyze the evolutionary conservation of individual amino acids present in the lipid-water-interface (LWI) regions and the relationship of TRPV4 with membrane cholesterol. Our data suggests that the positive-negative charges and hydrophobic-hydrophilic amino acids form "specific patterns" in the LWI region which remain conserved throughout the vertebrate evolution and thus suggesting for the specific microenvironment where TRPV4 remain functional. Notably, Spondylometaphyseal Dysplasia, Kozlowski (SMDK) disease causing L596P mutation disrupts this pattern significantly at the LWI region. L596P mutant also sequesters Caveolin-1 differently, especially in partial cholesterol-depleted (~40 % reduction) conditions. L596P shows altered localization in membrane and enhanced Ca2+-influx properties in cell as well as in filopodia-like structures. We propose that conserved pattern of amino acids is an important parameter for proper localization and functions of TRPV4 in physiological conditions. These findings also offer a new paradigm to analyze the channelopathies caused by mutations in LWI regions of other channels as well.


Assuntos
Doenças do Desenvolvimento Ósseo , Canalopatias , Canais de Cátion TRPV , Humanos , Aminoácidos , Doenças do Desenvolvimento Ósseo/genética , Canalopatias/genética , Colesterol/genética , Colesterol/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/química , Canais de Cátion TRPV/metabolismo
6.
J Mol Neurosci ; 72(8): 1598-1608, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35507012

RESUMO

Dry eye disease (DED) is a multifactorial disorder with recognized pathology, but not entirely known pathomechanism. It is suggested to represent a continuum with neuropathic corneal pain with the paradox that DED is a pain-free disease in most cases, although it is regarded as a pain condition. The current paper puts into perspective that one gateway from physiology to pathophysiology could be a Piezo2 channelopathy, opening the pathway to a potentially quad-phasic non-contact injury mechanism on a multifactorial basis and with a heterogeneous clinical picture. The primary non-contact injury phase could be the pain-free microinjury of the Piezo2 ion channel at the corneal somatosensory nerve terminal. The secondary non-contact injury phase involves harsher corneal tissue damage with C-fiber contribution due to the lost or inadequate intimate cross-talk between somatosensory Piezo2 and peripheral Piezo1. The third injury phase of this non-contact injury is the neuronal sensitization process with underlying repeated re-injury of the Piezo2, leading to the proposed chronic channelopathy. Notably, sensitization may evolve in certain cases in the absence of the second injury phase. Finally, the quadric injury phase is the lingering low-grade neuroinflammation associated with aging, called inflammaging. This quadric phase could clinically initiate or augment DED, explaining why increasing age is a risk factor. We highlight the potential role of the NGF-TrkA axis as a signaling mechanism that could further promote the microinjury of the corneal Piezo2 in a stress-derived hyperexcited state. The NGF-TrkA-Piezo2 axis might explain why female sex represents a risk factor for DED.


Assuntos
Canalopatias , Síndromes do Olho Seco , Canais Iônicos , Neuralgia , Caracteres Sexuais , Canalopatias/genética , Canalopatias/fisiopatologia , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/fisiopatologia , Feminino , Humanos , Canais Iônicos/genética , Masculino , Fator de Crescimento Neural/genética , Receptor trkA/genética
7.
Sci Signal ; 15(731): eabm6046, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35471943

RESUMO

Chronic pain is a major health issue, and the search for new analgesics has become increasingly important because of the addictive properties and unwanted side effects of opioids. To explore potentially new drug targets, we investigated mutations in the NTRK1 gene found in individuals with congenital insensitivity to pain with anhidrosis (CIPA). NTRK1 encodes tropomyosin receptor kinase A (TrkA), the receptor for nerve growth factor (NGF) and that contributes to nociception. Molecular modeling and biochemical analysis identified mutations that decreased the interaction between TrkA and one of its substrates and signaling effectors, phospholipase Cγ (PLCγ). We developed a cell-permeable phosphopeptide derived from TrkA (TAT-pQYP) that bound the Src homology domain 2 (SH2) of PLCγ. In HEK-293T cells, TAT-pQYP inhibited the binding of heterologously expressed TrkA to PLCγ and decreased NGF-induced, TrkA-mediated PLCγ activation and signaling. In mice, intraplantar administration of TAT-pQYP decreased mechanical sensitivity in an inflammatory pain model, suggesting that targeting this interaction may be analgesic. The findings demonstrate a strategy to identify new targets for pain relief by analyzing the signaling pathways that are perturbed in CIPA.


Assuntos
Hipo-Hidrose , Mutação , Insensibilidade Congênita à Dor , Fosfolipase C gama , Receptor trkA , Analgésicos/farmacologia , Animais , Canalopatias/genética , Canalopatias/metabolismo , Células HEK293 , Humanos , Hipo-Hidrose/genética , Hipo-Hidrose/metabolismo , Camundongos , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/farmacologia , Dor/genética , Dor/metabolismo , Insensibilidade Congênita à Dor/genética , Insensibilidade Congênita à Dor/metabolismo , Fosfolipase C gama/genética , Fosfolipase C gama/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo
8.
Crit Care Clin ; 38(2): 231-242, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35369945

RESUMO

The understanding and prevalence of cardiac channelopathies has grown over time. Many patients are asymptomatic but are at risk for malignant arrhythmias during high-acuity medical admissions. Long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia are discussed with specific consideration given for the role these medical conditions play during an intensive care unit admission-for either cardiac or noncardiac reasons.


Assuntos
Canalopatias , Taquicardia Ventricular , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Canalopatias/diagnóstico , Canalopatias/genética , Canalopatias/terapia , Morte Súbita Cardíaca , Humanos , Unidades de Terapia Intensiva , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/terapia
9.
Genes (Basel) ; 12(11)2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34828398

RESUMO

Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in KCNG1 affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for KCNG1 as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible KCNG1-related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes.


Assuntos
Doenças dos Bovinos/genética , Canalopatias/veterinária , Miotonia Congênita/veterinária , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Animais , Bovinos , Doenças dos Bovinos/patologia , Canalopatias/genética , Canalopatias/patologia , Endogamia , Mutação , Miotonia Congênita/genética , Miotonia Congênita/patologia , Fenótipo
10.
J Clin Immunol ; 41(5): 1004-1015, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33650027

RESUMO

Store-operated Ca2+ entry (SOCE) represents a predominant Ca2+ influx pathway in non-excitable cells. SOCE is required for immune cell activation and is mediated by the plasma membrane (PM) channel ORAI1 and the endoplasmic reticulum (ER) Ca2+ sensor STIM1. Mutations in the Orai1 or STIM1 genes abolish SOCE leading to combined immunodeficiency (CID), muscular hypotonia, and anhidrotic ectodermal dysplasia. Here, we identify a novel autosomal recessive mutation in ORAI1 in a child with CID. The patient is homozygous for p.C126R mutation in the second transmembrane domain (TM2) of ORAI1, a region with no previous loss-of-function mutations. SOCE is suppressed in the patient's lymphocytes, which is associated with impaired T cell proliferation and cytokine production. Functional analyses demonstrate that the p.C126R mutation does not alter protein expression but disrupts ORAI1 trafficking. Orai1-C126R does not insert properly into the bilayer resulting in ER retention. Insertion of an Arg on the opposite face of TM2 (L135R) also results in defective folding and trafficking. We conclude that positive side chains within ORAI1 TM2 are not tolerated and result in misfolding, defective bilayer insertion, and channel trafficking thus abolishing SOCE and resulting in CID.


Assuntos
Canalopatias/diagnóstico , Proteína ORAI1/genética , Doenças da Imunodeficiência Primária/diagnóstico , Cálcio/metabolismo , Proliferação de Células , Células Cultivadas , Canalopatias/genética , Canalopatias/imunologia , Citocinas/imunologia , Feminino , Humanos , Lactente , Mutação , Proteína ORAI1/química , Proteína ORAI1/metabolismo , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Transporte Proteico , Linfócitos T/imunologia
11.
Eur J Hum Genet ; 29(9): 1384-1395, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33594261

RESUMO

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.


Assuntos
Anormalidades Múltiplas/genética , Canalopatias/genética , Anormalidades Craniofaciais/genética , Canais de Potássio Éter-A-Go-Go/genética , Fibromatose Gengival/genética , Mutação com Ganho de Função , Hallux/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Unhas Malformadas/genética , Canais de Potássio/genética , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Polegar/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Canalopatias/patologia , Criança , Anormalidades Craniofaciais/patologia , Feminino , Fibromatose Gengival/patologia , Hallux/patologia , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/patologia , Masculino , Unhas Malformadas/patologia , Fenótipo , Polegar/patologia
12.
Nat Methods ; 17(12): 1245-1253, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33169015

RESUMO

Impaired protein stability or trafficking underlies diverse ion channelopathies and represents an unexploited unifying principle for developing common treatments for otherwise dissimilar diseases. Ubiquitination limits ion channel surface density, but targeting this pathway for the purposes of basic study or therapy is challenging because of its prevalent role in proteostasis. We developed engineered deubiquitinases (enDUBs) that enable selective ubiquitin chain removal from target proteins to rescue the functional expression of disparate mutant ion channels that underlie long QT syndrome (LQT) and cystic fibrosis (CF). In an LQT type 1 (LQT1) cardiomyocyte model, enDUB treatment restored delayed rectifier potassium currents and normalized action potential duration. CF-targeted enDUBs synergistically rescued common (ΔF508) and pharmacotherapy-resistant (N1303K) CF mutations when combined with the US Food and Drug Administation (FDA)-approved drugs Orkambi (lumacaftor/ivacaftor) and Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor). Altogether, targeted deubiquitination via enDUBs provides a powerful protein stabilization method that not only corrects diverse diseases caused by impaired ion channel trafficking, but also introduces a new tool for deconstructing the ubiquitin code in situ.


Assuntos
Canalopatias/patologia , Fibrose Cística/patologia , Enzimas Desubiquitinantes/metabolismo , Transporte de Íons/fisiologia , Síndrome do QT Longo/patologia , Canais de Potássio/fisiologia , Aminofenóis/farmacologia , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Canalopatias/genética , Fibrose Cística/genética , Enzimas Desubiquitinantes/genética , Combinação de Medicamentos , Humanos , Indóis/farmacologia , Transporte de Íons/genética , Síndrome do QT Longo/genética , Miócitos Cardíacos/fisiologia , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Canais de Potássio/genética , Pirazóis/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Quinolonas/farmacologia
13.
J Comput Neurosci ; 48(4): 377-386, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33063225

RESUMO

Channelopathies involving acquired or genetic modifications of the delayed rectifier K+ channel Kv1.1 include phenotypes characterized by enhanced neuronal excitability. Affected Kv1.1 channels exhibit combinations of altered expression, voltage sensitivity, and rates of activation and deactivation. Computational modeling and analysis can reveal the potential of particular channelopathies to alter neuronal excitability. A dynamical systems approach was taken to study the excitability and underlying dynamical structure of the Hodgkin-Huxley (HH) model of neural excitation as properties of the delayed rectifier K+ channel were altered. Bifurcation patterns of the HH model were determined as the amplitude of steady injection current was varied simultaneously with single parameters describing the delayed rectifier rates of activation and deactivation, maximal conductance, and voltage sensitivity. Relatively modest changes in the properties of the delayed rectifier K+ channel analogous to what is described for its channelopathies alter the bifurcation structure of the HH model and profoundly modify excitability of the HH model. Channelopathies associated with Kv1.1 can reduce the threshold for onset of neural activity. These studies also demonstrate how pathological delayed rectifier K+ channels could lead to the observation of the generalized Hopf bifurcation and, perhaps, other variants of the Hopf bifurcation. The observed bifurcation patterns collectively demonstrate that properties of the nominal delayed rectifier in the HH model appear optimized to permit activation of the HH model over the broadest possible range of input currents.


Assuntos
Canalopatias/fisiopatologia , Canais de Potássio de Retificação Tardia/genética , Potenciais da Membrana/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Animais , Canalopatias/genética , Simulação por Computador
14.
Int J Mol Sci ; 21(18)2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967234

RESUMO

Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. In the eye, ion channels are involved in various physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to an array of blindness, termed ocular channelopathies. These mutations result in either a loss- or gain-of channel functions affecting the structure, assembly, trafficking, and localization of channel proteins. A dominant-negative effect is caused in a few channels formed by the assembly of several subunits that exist as homo- or heteromeric proteins. Here, we review the role of different mutations in switching a "sensing" ion channel to "non-sensing," leading to ocular channelopathies like Leber's congenital amaurosis 16 (LCA16), cone dystrophy, congenital stationary night blindness (CSNB), achromatopsia, bestrophinopathies, retinitis pigmentosa, etc. We also discuss the various in vitro and in vivo disease models available to investigate the impact of mutations on channel properties, to dissect the disease mechanism, and understand the pathophysiology. Innovating the potential pharmacological and therapeutic approaches and their efficient delivery to the eye for reversing a "non-sensing" channel to "sensing" would be life-changing.


Assuntos
Canalopatias , Oftalmopatias Hereditárias , Doenças Genéticas Ligadas ao Cromossomo X , Canais Iônicos , Amaurose Congênita de Leber , Miopia , Cegueira Noturna , Retinose Pigmentar , Animais , Canalopatias/genética , Canalopatias/metabolismo , Canalopatias/patologia , Canalopatias/terapia , Modelos Animais de Doenças , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/metabolismo , Oftalmopatias Hereditárias/patologia , Oftalmopatias Hereditárias/terapia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Canais Iônicos/genética , Canais Iônicos/metabolismo , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/metabolismo , Amaurose Congênita de Leber/patologia , Amaurose Congênita de Leber/terapia , Miopia/genética , Miopia/metabolismo , Miopia/patologia , Miopia/terapia , Cegueira Noturna/genética , Cegueira Noturna/metabolismo , Cegueira Noturna/patologia , Cegueira Noturna/terapia , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo , Retinose Pigmentar/patologia , Retinose Pigmentar/terapia
15.
Herzschrittmacherther Elektrophysiol ; 31(4): 394-400, 2020 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-32661562

RESUMO

A variety of arrhythmogenic cardiac diseases such as channelopathies and cardiomyopathies are caused by genetic alterations. In patients with these diseases, malignant arrhythmias or sudden cardiac death frequently manifest already during young adulthood. Early recognition, risk stratification and adequate therapy is therefore essential to avoid sudden cardiac death. This review summarizes the implications of genetic testing for diagnosis, risk stratification and therapy of patients with cardiac channelopathies (long-QT syndrome, short-QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia) and inherited cardiomyopathies (hypertrophic, dilatative or arrhythmogenic right ventricular cardiomyopathy).


Assuntos
Síndrome de Brugada , Canalopatias , Síndrome do QT Longo , Taquicardia Ventricular , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Canalopatias/diagnóstico , Canalopatias/genética , Morte Súbita Cardíaca/prevenção & controle , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genética , Taquicardia Ventricular/terapia , Adulto Jovem
16.
Adv Genet ; 105: 137-174, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32560786

RESUMO

Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.


Assuntos
Anormalidades Múltiplas/genética , Síndrome de Andersen/genética , Cardiomegalia/genética , Canalopatias/genética , Anormalidades Craniofaciais/genética , Fibromatose Gengival/genética , Hallux/anormalidades , Deformidades Congênitas da Mão/genética , Hipertricose/genética , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Unhas Malformadas/genética , Osteocondrodisplasias/genética , Canais de Potássio/genética , Polegar/anormalidades , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Síndrome de Andersen/tratamento farmacológico , Síndrome de Andersen/patologia , Síndrome de Andersen/fisiopatologia , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Canalopatias/tratamento farmacológico , Canalopatias/metabolismo , Canalopatias/fisiopatologia , Criança , Anormalidades Craniofaciais/tratamento farmacológico , Anormalidades Craniofaciais/patologia , Anormalidades Craniofaciais/fisiopatologia , Fibromatose Gengival/tratamento farmacológico , Fibromatose Gengival/patologia , Fibromatose Gengival/fisiopatologia , Hallux/patologia , Hallux/fisiopatologia , Deformidades Congênitas da Mão/tratamento farmacológico , Deformidades Congênitas da Mão/patologia , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Hipertricose/tratamento farmacológico , Hipertricose/patologia , Hipertricose/fisiopatologia , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Hipotonia Muscular/tratamento farmacológico , Hipotonia Muscular/patologia , Hipotonia Muscular/fisiopatologia , Unhas Malformadas/tratamento farmacológico , Unhas Malformadas/patologia , Unhas Malformadas/fisiopatologia , Osteocondrodisplasias/tratamento farmacológico , Osteocondrodisplasias/patologia , Osteocondrodisplasias/fisiopatologia , Canais de Potássio/metabolismo , Polegar/patologia , Polegar/fisiopatologia
17.
Pflugers Arch ; 472(7): 755-773, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32583268

RESUMO

The identification of rare disease-causing variants in humans by large-scale next-generation sequencing (NGS) studies has also provided us with new insights into the pathophysiological role of de novo missense variants in the CACNA1D gene that encodes the pore-forming α1-subunit of voltage-gated Cav1.3 L-type Ca2+ channels. These CACNA1D variants have been identified somatically in aldosterone-producing adenomas as well as germline in patients with neurodevelopmental and in some cases endocrine symptoms. In vitro studies in heterologous expression systems have revealed typical gating changes that indicate enhanced Ca2+ influx through Cav1.3 channels as the underlying disease-causing mechanism. Here we summarize the clinical findings of 12 well-characterized individuals with a total of 9 high-risk pathogenic CACNA1D variants. Moreover, we propose how information from somatic mutations in aldosterone-producing adenomas could be used to predict the potential pathogenicity of novel germline variants. Since these pathogenic de novo variants can cause a channel-gain-of function, we also discuss the use of L-type Ca2+ channel blockers as a potential therapeutic option.


Assuntos
Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Canalopatias/genética , Canalopatias/metabolismo , Animais , Humanos , Mutação/genética , Fenótipo
18.
Pflugers Arch ; 472(7): 739-754, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32222817

RESUMO

CaV1.1 is specifically expressed in skeletal muscle where it functions as voltage sensor of skeletal muscle excitation-contraction (EC) coupling independently of its functions as L-type calcium channel. Consequently, all known CaV1.1-related diseases are muscle diseases and the molecular and cellular disease mechanisms relate to the dual functions of CaV1.1 in this tissue. To date, four types of muscle diseases are known that can be linked to mutations in the CACNA1S gene or to splicing defects. These are hypo- and normokalemic periodic paralysis, malignant hyperthermia susceptibility, CaV1.1-related myopathies, and myotonic dystrophy type 1. In addition, the CaV1.1 function in EC coupling is perturbed in Native American myopathy, arising from mutations in the CaV1.1-associated protein STAC3. Here, we first address general considerations concerning the possible roles of CaV1.1 in disease and then discuss the state of the art regarding the pathophysiology of the CaV1.1-related skeletal muscle diseases with an emphasis on molecular disease mechanisms.


Assuntos
Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Canalopatias/genética , Canalopatias/metabolismo , Músculo Esquelético/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Canalopatias/patologia , Humanos , Músculo Esquelético/patologia , Mutação/genética
19.
BMC Neurol ; 19(1): 246, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640633

RESUMO

BACKGROUND: To describe a patient with sleep alleviated episodic ataxia type 2 with a novel CACNA1A pathogenic variant and provide a possible link to sleep responsive migraine. CASE PRESENTATION: A 26-year-old woman with recurrent attacks of dizziness, nausea, vomiting, ataxia and dysarthria presented for a possible diagnosis of vestibular migraine. Unique to her attacks was if she could fall asleep for as little as 15 min the spells would subside. If however she remained awake the attacks would continue unabated. A presumed diagnosis of episodic ataxia type 2 was made and she became attack free on acetazolamide without recurrence. Genetic testing demonstrated a novel pathogenic variant in CACNA1A on chromosome 19. This pathogenic variant has not been previously reported in the literature and is suggested to truncate the CACNA1A polypeptide by introducing a premature stop codon. CONCLUSION: A case of episodic ataxia type 2 with a novel pathogenic variant in CACNA1A is described. Interestingly, the patient's symptoms would completely alleviate with sleep which suggests a sleep modulated channelopathy. The mechanisms by which sleep could potentially alter this pathogenic variant are hypothesized. A potential link to sleep alleviated migraine is suggested. Further study of this novel pathogenic variant may help us understand not only how sleep can modulate episodic ataxia type 2, but also migraine.


Assuntos
Ataxia/genética , Canais de Cálcio/genética , Sono , Acetazolamida/uso terapêutico , Adulto , Ataxia/complicações , Ataxia/tratamento farmacológico , Inibidores da Anidrase Carbônica/uso terapêutico , Canalopatias/genética , Códon sem Sentido , Feminino , Humanos , Transtornos de Enxaqueca/genética , Linhagem
20.
Cell Calcium ; 80: 112-116, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31009822

RESUMO

Ca2+ release-activated Ca2+ (CRAC) channels are intimately linked with health and disease. The gene encoding the CRAC channel, ORAI1, was discovered in part by genetic analysis of patients with abolished CRAC channel function. And patients with autosomal recessive loss-of-function (LOF) mutations in ORAI1 and its activator stromal interaction molecule 1 (STIM1) that abolish CRAC channel function and store-operated Ca2+ entry (SOCE) define essential functions of CRAC channels in health and disease. Conversely, gain-of-function (GOF) mutations in ORAI1 and STIM1 are associated with tubular aggregate myopathy (TAM) and Stormorken syndrome due to constitutive CRAC channel activation. In addition, genetically engineered animal models of ORAI and STIM function have provided important insights into the physiological and pathophysiological roles of CRAC channels in cell types and organs beyond those affected in human patients. The picture emerging from this body of work shows CRAC channels as important regulators of cell function in many tissues, and as potential drug targets for the treatment of autoimmune and inflammatory disorders.


Assuntos
Transtornos Plaquetários/metabolismo , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Canalopatias/metabolismo , Dislexia/metabolismo , Ictiose/metabolismo , Transtornos de Enxaqueca/metabolismo , Miose/metabolismo , Mutação/genética , Miopatias Congênitas Estruturais/metabolismo , Proteínas de Neoplasias/genética , Proteína ORAI1/genética , Baço/anormalidades , Molécula 1 de Interação Estromal/genética , Animais , Transtornos Plaquetários/tratamento farmacológico , Transtornos Plaquetários/genética , Cálcio/metabolismo , Sinalização do Cálcio , Canalopatias/tratamento farmacológico , Canalopatias/genética , Modelos Animais de Doenças , Descoberta de Drogas , Dislexia/tratamento farmacológico , Dislexia/genética , Eritrócitos Anormais/metabolismo , Humanos , Ictiose/tratamento farmacológico , Ictiose/genética , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/genética , Miose/tratamento farmacológico , Miose/genética , Fadiga Muscular/genética , Miopatias Congênitas Estruturais/tratamento farmacológico , Miopatias Congênitas Estruturais/genética , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/metabolismo , Baço/metabolismo , Molécula 1 de Interação Estromal/metabolismo
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