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Network topology of NaV1.7 mutations in sodium channel-related painful disorders

Dimos Kapetis, Jenny Sassone, Yang Yang, Barbara Galbardi, Markos N. Xenakis, Ronald L. Westra, Radek Szklarczyk, Patrick Lindsey, Catharina G. Faber, Monique Gerrits, Ingemar S. J. Merkies, Sulayman D. Dib-Hajj (+3 others)
2017 BMC Systems Biology  
Conclusions: Our in-silico analyses predict that pain-related pathogenic NaV1.7 mutations may affect the network topological properties of the protein and suggest |ΔB ct | value as a potential in-silico  ...  on behalf of the PROPANE Study Group Abstract Background: Gain-of-function mutations in SCN9A gene that encodes the voltage-gated sodium channel NaV1.7 have been associated with a wide spectrum of painful  ...  Acknowledgements We acknowledge the other members of the PROPANE (Probing the role of sodium channels in painful neuropathies) study group: Michela Taiana Funding The study was financed by institutional  ... 
doi:10.1186/s12918-016-0382-0 pmid:28235406 pmcid:PMC5324268 fatcat:ivsi3ukjojeb3auzxnbuevc6ze

Hydropathicity-based prediction of pain-causing NaV1.7 variants

Makros N Xenakis, Dimos Kapetis, Yang Yang, Monique M Gerrits, Jordi Heijman, Stephen G Waxman, Giuseppe Lauria, Catharina G Faber, Ronald L Westra, Patrick J Lindsey, Hubert J Smeets
2021 BMC Bioinformatics  
Mutation-induced variations in the functional architecture of the NaV1.7 channel protein are causally related to a broad spectrum of human pain disorders.  ...  In this work, we utilize spatial complexity of hydropathic effects toward predicting which NaV1.7 variants cause pain (and which are neutral) based on the location of corresponding mutation sites within  ...  pain-related mutations.  ... 
doi:10.1186/s12859-021-04119-2 pmid:33892629 fatcat:h2ilnjuyhngnlfdghbllg3lwre

Computational Pipeline to probe NaV1.7 gain-of-functions variants in neuropathic painful syndromes [article]

Alberto Toffano, Giacomo Chiarot, Stefano Zamuner, Margherita Marchi, Erika Salvi, Stephen G. Waxman, Catharina G. Faber, Giuseppe Lauria, Achille Giacometti, Marta Simeoni
2020 arXiv   pre-print
We apply this concept to the analysis of variants in sodium channel NaV1.7 subunit found in patients with chronic painful syndromes, by the implementation of a dedicated computational pipeline empowering  ...  Their employment to investigate the effect of mutational changes in genes encoding for proteins modulating the membrane of excitable cells, whose biological correlates are assessed at electrophysiological  ...  The use of the SCSCF multiprocessor cluster at the Università Ca' Foscari Venezia is gratefully acknowledged.  ... 
arXiv:2010.01607v1 fatcat:dho5lzgpkbc5bedwkeoqj5d2zy

Computational pipeline to probe NaV1.7 gain-of-function variants in neuropathic painful syndromes

Alberto A. Toffano, Giacomo Chiarot, Stefano Zamuner, Margherita Marchi, Erika Salvi, Stephen G. Waxman, Catharina G. Faber, Giuseppe Lauria, Achille Giacometti, Marta Simeoni
2020 Scientific Reports  
We apply this concept to the analysis of variants in sodium channel NaV1.7 subunit found in patients with chronic painful syndromes, by the implementation of a dedicated computational pipeline empowering  ...  Their employment to investigate the effect of mutational changes in genes encoding for proteins modulating the membrane of excitable cells, whose biological correlates are assessed at electrophysiological  ...  The work was supported by MIUR PRIN-COFIN2017 Soft Adaptive Networks grant 2017Z55KCW (A.G).  ... 
doi:10.1038/s41598-020-74591-y pmid:33087732 pmcid:PMC7578092 fatcat:bwskpvstibgvjfifaqr56r37dy

Gene variant effects across sodium channelopathies predict function and guide precision therapy

Andreas Brunklaus, Tony Feng, Tobias Brünger, Eduardo Perez-Palma, Henrike Heyne, Emma Matthews, Christopher Semsarian, Joseph D. Symonds, Sameer M. Zuberi, Dennis Lal, Stephanie Schorge
2022 Brain  
Pathogenic variants in the voltage-gated sodium channel gene family (SCNs) lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac  ...  Given the evolutionarily conserved nature of the sodium channel genes we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function  ...  Nav1.7 mutations associated with N paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navbeta4 peptide-mediated A resurgent sodium currents. J Physiol.  ... 
doi:10.1093/brain/awac006 pmid:35037686 fatcat:bjafz3tr4zb7fjjsnbzd4n53nu

Prediction and optimization of NaV1.7 inhibitors based on machine learning methods [article]

Weikaixin Kong, Xinyu Tu, Zhengwei Xie, Zhuo Huang
2020 arXiv   pre-print
However, because the model evaluation method in this article is not comprehensive enough, there is still a lot of research work to be performed, such as comparison with other existing methods.  ...  We used machine learning methods to predict NaV1.7 inhibitors and found the model RF-CDK that performed best on the imbalanced dataset.  ...  Acknowledgements Author Contributions Statement All authors contributed to the work presented in this paper.  ... 
arXiv:1912.05903v2 fatcat:kmdouq74ejffhoswefkcocez7y

Rare Nav1.7 variants associated with painful diabetic peripheral neuropathy

Iulia Blesneac, Andreas C. Themistocleous, Carl Fratter, Linus J. Conrad, Juan D. Ramirez, James J. Cox, Solomon Tesfaye, Pallai R. Shillo, Andrew S.C. Rice, Stephen J. Tucker, David L.H. Bennett
2017 Pain  
Here, we examined the relationship between variants in the voltage-gated sodium channel Na V 1.7 and NeuP in a deeply phenotyped cohort of patients with DPN.  ...  Five of these variants had previously been described in the context of other NeuP disorders and 7 have not previously been linked to NeuP.  ...  and severity of pain in acquired pain disorders.  ... 
doi:10.1097/j.pain.0000000000001116 pmid:29176367 pmcid:PMC5828379 fatcat:e6rxrmehy5c7rbyjuwamgtaqw4

Defining the Functional Role of NaV1.7 in Human Nociception

Lucy A. McDermott, Greg A. Weir, Andreas C. Themistocleous, Andrew R. Segerdahl, Iulia Blesneac, Georgios Baskozos, Alex J. Clark, Val Millar, Liam J. Peck, Daniel Ebner, Irene Tracey, Jordi Serra (+1 others)
2019 Neuron  
Loss-of-function mutations in NaV1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development.  ...  Utilizing a multi-modal approach, we investigated how NaV1.7 mutations lead to human pain insensitivity.  ...  INTRODUCTION Bi-allelic inactivating mutations in SCN9A, which encodes the voltage-gated sodium channel (VGSC) Na V 1.7, result in the striking clinical phenotype of congenital insensitivity to pain (CIP  ... 
doi:10.1016/j.neuron.2019.01.047 pmid:30795902 pmcid:PMC6424805 fatcat:jsm6usu7gbgtlpr2h2gzrlyuxu

Multiple chronic pain states are associated with a common amino acid–changing allele in KCNS1

Michael Costigan, Inna Belfer, Robert S. Griffin, Feng Dai, Lee B. Barrett, Giovanni Coppola, Tianxia Wu, Carly Kiselycznyk, Minakshi Poddar, Yan Lu, Luda Diatchenko, Shad Smith (+14 others)
2010 Brain  
KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans.  ...  This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve  ...  Acknowledgement The authors would like to dedicate this manuscript to the memory of their friend and collaborator Mitchell Max.  ... 
doi:10.1093/brain/awq195 pmid:20724292 pmcid:PMC2929335 fatcat:lnv34pecq5abnlhkqkrfbezz5m

A selective naV1.1 activator with potential for treatment of dravet syndrome epilepsy

Chun Y. Chow, Yanni K.Y. Chin, Linlin Ma, Eivind A.B. Undheim, Volker Herzig, Glenn F. King
2020 Biochemical Pharmacology  
Heterozygous loss-of-function mutations in one allele of SCN1A, the gene encoding the voltage-gated sodium channel 1.1 (NaV1.1), lead to DS.  ...  We hypothesised that DS symptoms could be ameliorated by a drug that activates the reduced population of functional NaV1.1 channels in DS interneurons.  ...  NaV channels have become major therapeutic targets for treatment of a range of nervous system disorders.  ... 
doi:10.1016/j.bcp.2020.113991 pmid:32335140 fatcat:2wqbgxfcsfaoxh6wbnbuureyuq

NOCICEPTRA: Gene and microRNA Signatures and Their Trajectories Characterizing Human iPSC‐Derived Nociceptor Maturation

Maximilian Zeidler, Kai K. Kummer, Clemens L. Schöpf, Theodora Kalpachidou, Georg Kern, M. Zameel Cader, Michaela Kress
2021 Advanced Science  
Nociceptors are primary afferent neurons serving the reception of acute pain but also the transit into maladaptive pain disorders.  ...  iDNs. mRNA and miRNA candidates emerge as regulatory hubs for neurite outgrowth, synapse development, and ion channel expression.  ...  Tschugg of the IT Services, Medical University of Innsbruck, for providing general support regarding the computing environment.  ... 
doi:10.1002/advs.202102354 pmid:34486248 pmcid:PMC8564443 fatcat:2tedzx5bvjgkjeixygztmepmum

Building sensory axons: Delivery and distribution of NaV1.7 channels and effects of inflammatory mediators

Elizabeth J. Akin, Grant P. Higerd, Malgorzata A. Mis, Brian S. Tanaka, Talia Adi, Shujun Liu, Fadia B. Dib-Hajj, Stephen G. Waxman, Sulayman D. Dib-Hajj
2019 Science Advances  
Sodium channel NaV1.7 controls firing of nociceptors, and its role in human pain has been validated by genetic and functional studies.  ...  We also demonstrate that inflammatory mediators trigger an increase in the number of NaV1.7-carrying vesicles per axon, a threefold increase in the median number of NaV1.7 channels per vesicle and a ~50%  ...  Additional data related to this paper may be requested from the authors.  ... 
doi:10.1126/sciadv.aax4755 pmid:31681845 pmcid:PMC6810356 fatcat:volpl7cwsvgwvaiidzwevlg6ja

NOCICEPTRA: Gene and microRNA signatures and their trajectories characterizing human iPSC-derived nociceptor maturation [article]

Maximilian Zeidler, Kai K. Kummer, Clemens L. Schoepf, Theodora Kalpachidou, Georg Kern, M. Zameel Cader, Michaela Kress
2021 bioRxiv   pre-print
Nociceptors are primary afferent neurons serving the reception of acute pain but also the transit into maladaptive pain disorders.  ...  iDNs. mRNA and miRNA candidates emerged as regulatory hubs for neurite outgrowth, synapse development and ion channel expression.  ...  Since a number of severe human pain disorders are strongly associated with gain or loss-offunction mutations of ion channels in neurons (59-63), we applied the NOCICEPTRA tool to exemplarily investigate  ... 
doi:10.1101/2021.06.07.447056 fatcat:75zusfd7gvexta62mangklcln4

Calcium-Permeable Ion Channels in Pain Signaling

Emmanuel Bourinet, Christophe Altier, Michael E. Hildebrand, Tuan Trang, Michael W. Salter, Gerald W. Zamponi
2014 Physiological Reviews  
The detection and processing of painful stimuli in afferent sensory neurons is critically dependent on a wide range of different types of voltage-and ligand-gated ion channels, including sodium, calcium  ...  In this article, we provide a broad overview of different calcium-permeable ion channels in the afferent pain pathway and their role in pain pathophysiology.  ...  All six Pakistani children shared a null mutation in the Nav1.7 sodium channel, thus losing all ability to sense thermal and mechanical pain (204) .  ... 
doi:10.1152/physrev.00023.2013 pmid:24382884 fatcat:4m7m4jcg6fgurp4a3cpcuei3fa

ION CHANNELS OF NOCICEPTION

Edwin W. McCleskey, Michael S. Gold
1999 Annual Review of Physiology  
His main research interests are molecular and cellular mechanisms of pain, migraine pathophysiology, synaptic transmission, ligand-gated receptors, desensitization, and signalling via reactive oxygen species  ...  elected as Professor of Cell Biology at the University of Eastern Finland.  ...  Greutert for technical assistance in the study. Conflicts of Interest: The authors declare no conflict of interest.  ... 
doi:10.1146/annurev.physiol.61.1.835 pmid:10099712 fatcat:6cukvjnt3verlc26x7gm7bxooy
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