TY - JOUR
T1 - Network topology of NaV1.7 mutations in sodium channel-related painful disorders
AU - Kapetis, Dimos
AU - Kapetis, Dimos
AU - Sassone, Jenny
AU - Sassone, Jenny
AU - Yang, Yang
AU - Yang, Yang
AU - Galbardi, Barbara
AU - Xenakis, Markos N.
AU - Xenakis, Markos N.
AU - Westra, Ronald L.
AU - Westra, Ronald L.
AU - Szklarczyk, Radek
AU - Lindsey, Patrick
AU - Faber, Catharina G.
AU - Faber, Catharina G.
AU - Gerrits, Monique
AU - Merkies, Ingemar S.J.
AU - Merkies, Ingemar S.J.
AU - Dib-Hajj, Sulayman D.
AU - Dib-Hajj, Sulayman D.
AU - Mantegazza, Massimo
AU - Waxman, Stephen G.
AU - Waxman, Stephen G.
AU - Lauria, Giuseppe
AU - Taiana, Michela
AU - Marchi, Margherita
AU - Lombardi, Raffaella
AU - Cazzato, Daniele
AU - Boneschi, Filippo Martinelli
AU - Zauli, Andrea
AU - Clarelli, Ferdinando
AU - Santoro, Silvia
AU - Lopez, Ignazio
AU - Quattrini, Angelo
AU - Hoeijmakers, Janneke
AU - Sopacua, Maurice
AU - de Greef, Bianca
AU - Smeets, Hubertus Julius Maria
AU - Momani, Rowida Al
AU - Vanoevelen, Jo Michel
AU - Eijkenboom, Ivo
AU - Cestèle, Sandrine
AU - Chever, Oana
AU - Malik, Rayaz
AU - Tavakoli, Mitra
AU - Ziegler, Dan
PY - 2017/2/24
Y1 - 2017/2/24
N2 - © 2017 The Author(s). 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 syndromes in humans including inherited erythromelalgia, paroxysmal extreme pain disorder and small fibre neuropathy. These mutations change the biophysical properties of NaV1.7 channels leading to hyperexcitability of dorsal root ganglion nociceptors and pain symptoms. There is a need for better understanding of how gain-of-function mutations alter the atomic structure of Nav1.7. Results: We used homology modeling to build an atomic model of NaV1.7 and a network-based theoretical approach, which can predict interatomic interactions and connectivity arrangements, to investigate how pain-related NaV1.7 mutations may alter specific interatomic bonds and cause connectivity rearrangement, compared to benign variants and polymorphisms. For each amino acid substitution, we calculated the topological parameters betweenness centrality (B ct ), degree (D), clustering coefficient (CC ct ), closeness (C ct ), and eccentricity (E ct ), and calculated their variation ( value = mutant value -WT value ). Pathogenic NaV1.7 mutations showed significantly higher variation of |B ct | compared to benign variants and polymorphisms. Using the cut-off value ±0.26 calculated by receiver operating curve analysis, we found that B ct correctly differentiated pathogenic NaV1.7 mutations from variants not causing biophysical abnormalities (nABN) and homologous SNPs (hSNPs) with 76% sensitivity and 83% specificity. Conclusions: Our in-silico analyses predict that pain-related pathogenic NaV1.7 mutations may affect the network topological properties of the protein and suggest |B ct | value as a potential in-silico marker.
AB - © 2017 The Author(s). 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 syndromes in humans including inherited erythromelalgia, paroxysmal extreme pain disorder and small fibre neuropathy. These mutations change the biophysical properties of NaV1.7 channels leading to hyperexcitability of dorsal root ganglion nociceptors and pain symptoms. There is a need for better understanding of how gain-of-function mutations alter the atomic structure of Nav1.7. Results: We used homology modeling to build an atomic model of NaV1.7 and a network-based theoretical approach, which can predict interatomic interactions and connectivity arrangements, to investigate how pain-related NaV1.7 mutations may alter specific interatomic bonds and cause connectivity rearrangement, compared to benign variants and polymorphisms. For each amino acid substitution, we calculated the topological parameters betweenness centrality (B ct ), degree (D), clustering coefficient (CC ct ), closeness (C ct ), and eccentricity (E ct ), and calculated their variation ( value = mutant value -WT value ). Pathogenic NaV1.7 mutations showed significantly higher variation of |B ct | compared to benign variants and polymorphisms. Using the cut-off value ±0.26 calculated by receiver operating curve analysis, we found that B ct correctly differentiated pathogenic NaV1.7 mutations from variants not causing biophysical abnormalities (nABN) and homologous SNPs (hSNPs) with 76% sensitivity and 83% specificity. Conclusions: Our in-silico analyses predict that pain-related pathogenic NaV1.7 mutations may affect the network topological properties of the protein and suggest |B ct | value as a potential in-silico marker.
KW - Network analysis
KW - Neuropathic pain
KW - Sodium channel
KW - Structural modeling
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U2 - 10.1186/s12918-016-0382-0
DO - 10.1186/s12918-016-0382-0
M3 - Article
C2 - 28235406
AN - SCOPUS:85013755191
VL - 11
JO - BMC Systems Biology
JF - BMC Systems Biology
SN - 1752-0509
IS - 1
ER -