Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV1.7

被引:91
作者
Estacion, Mark [1 ,2 ]
Han, Chongyang [1 ,2 ]
Choi, Jin-Sung [1 ,2 ,8 ]
Hoeijmakers, Janneke G. J. [3 ]
Lauria, Giuseppe [4 ]
Drenth, Joost P. H. [5 ]
Gerrits, Monique M. [6 ]
Dib-Hajj, Sulayman D. [1 ,2 ]
Faber, Catharina G. [3 ]
Merkies, Ingemar S. J. [3 ,7 ]
Waxman, Stephen G. [1 ]
机构
[1] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA
[2] Vet Affairs Med Ctr, Ctr Neurosci & Regenerat Res, West Haven, CT 06516 USA
[3] Univ Med Ctr Maastricht, Dept Neurol, Maastricht, Netherlands
[4] IRCCS Fdn, Neuromuscular Dis Unit, Milan, Italy
[5] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol & Hepatol, NL-6525 ED Nijmegen, Netherlands
[6] Univ Med Ctr Maastricht, Dept Clin Genet, Maastricht, Netherlands
[7] Spaarne Hosp, Dept Neurol, Hoofddorp, Netherlands
[8] Catholic Univ Korea, Coll Pharm, Puchon, South Korea
关键词
SMALL-FIBER NEUROPATHY; SODIUM-CHANNEL MUTATION; PERIPHERAL NEUROPATHY; DIAGNOSTIC-CRITERIA; SCN9A MUTATIONS; DISORDER; NEURONS; ERYTHROMELALGIA; ERYTHERMALGIA; POLYMORPHISM;
D O I
10.1186/1744-8069-7-92
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Background: Sodium channel Na(V)1.7 is preferentially expressed within dorsal root ganglia (DRG), trigeminal ganglia and sympathetic ganglion neurons and their fine-diamter axons, where it acts as a threshold channel, amplifying stimuli such as generator potentials in nociceptors. Gain-of-function mutations and variants (single amino acid substitutions) of NaV1.7 have been linked to three pain syndromes: Inherited Erythromelalgia (IEM), Paroxysmal Extreme Pain Disorder (PEPD), and Small Fiber Neuropathy (SFN). IEM is characterized clinically by burning pain and redness that is usually focused on the distal extremities, precipitated by mild warmth and relieved by cooling, and is caused by mutations that hyperpolarize activation, slow deactivation, and enhance the channel ramp response. PEPD is characterized by perirectal, periocular or perimandibular pain, often triggered by defecation or lower body stimulation, and is caused by mutations that severely impair fast-inactivation. SFN presents a clinical picture dominated by neuropathic pain and autonomic symptoms; gain-of-function variants have been reported to be present in approximately 30% of patients with biopsy-confirmed idiopathic SFN, and functional testing has shown altered fast-inactivation, slow-inactivation or resurgent current. In this paper we describe three patients who house the Na(V)1.7/I228M variant. Methods: We have used clinical assessment of patients, quantitative sensory testing and skin biopsy to study these patients, including two siblings in one family, in whom genomic screening demonstrated the I228M Na(V)1.7 variant. Electrophysiology (voltage-clamp and current-clamp) was used to test functional effects of the variant channel. Results: We report three different clinical presentations of the I228M Na(V)1.7 variant: presentation with severe facial pain, presentation with distal (feet, hands) pain, and presentation with scalp discomfort in three patients housing this Na(V)1.7 variant, two of which are from a single family. We also demonstrate that the Na(V)1.7/I228M variant impairs slow-inactivation, and produces hyperexcitability in both trigeminal ganglion and DRG neurons. Conclusion: Our results demonstrate intra-and interfamily phenotypic diversity in pain syndromes produced by a gain-of-function variant of Na(V)1.7.
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页数:10
相关论文
共 39 条
[1]   Intraepidermal nerve fiber density and its application in sarcoidosis [J].
Bakkers, M. ;
Merkies, I. S. J. ;
Lauria, G. ;
Devigili, G. ;
Penza, P. ;
Lombardi, R. ;
Hermans, M. C. E. ;
van Nes, S. I. ;
De Baets, M. ;
Faber, C. G. .
NEUROLOGY, 2009, 73 (14) :1142-1148
[2]   Mitochondrial dynamics and peripheral neuropathy [J].
Baloh, Robert H. .
NEUROSCIENTIST, 2008, 14 (01) :12-18
[3]   Etiology of small-fiber neuropathy [J].
Bednarik, Josef ;
Vlckova-Moravcova, Eva ;
Bursova, Sarka ;
Belobradkova, Jana ;
Dusek, Ladislav ;
Sommer, Claudia .
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, 2009, 14 (03) :177-183
[4]   International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels [J].
Catterall, WA ;
Goldin, AL ;
Waxman, SG .
PHARMACOLOGICAL REVIEWS, 2005, 57 (04) :397-409
[5]   Inherited erythermalgia - Limb pain from an S4 charge-neutral Na channelopathy [J].
Choi, Jin-Sung ;
Dib-Hajj, Sulayman D. ;
Waxman, Stephen G. .
NEUROLOGY, 2006, 67 (09) :1563-1567
[6]   Alternative splicing may contribute to time-dependent manifestation of inherited erythromelalgia [J].
Choi, Jin-Sung ;
Cheng, Xiaoyang ;
Foster, Edmund ;
Leffler, Andreas ;
Tyrrell, Lynda ;
te Morsche, Rene H. M. ;
Eastman, Emmanuella M. ;
Jansen, Henry J. ;
Huehne, Kathrin ;
Nau, Carla ;
Dib-Hajj, Sulayman D. ;
Drenth, Joost P. H. ;
Waxman, Stephen G. .
BRAIN, 2010, 133 :1823-1835
[7]  
Cummins TR, 1998, J NEUROSCI, V18, P9607
[8]   The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology [J].
Devigili, Grazia ;
Tugnoli, Valeria ;
Penza, Paola ;
Camozzi, Francesca ;
Lombardi, Raffaella ;
Melli, Giorgia ;
Broglio, Laura ;
Granieri, Enrico ;
Lauria, Giuseppe .
BRAIN, 2008, 131 :1912-1925
[9]   Sodium Channels in Normal and Pathological Pain [J].
Dib-Hajj, Sulayman D. ;
Cummins, Theodore R. ;
Black, Joel A. ;
Waxman, Stephen G. .
ANNUAL REVIEW OF NEUROSCIENCE, VOL 33, 2010, 33 :325-347
[10]   Transfection of rat or mouse neurons by biolistics or electroporation [J].
Dib-Hajj, Sulayman D. ;
Choi, Jin Sung ;
Macala, Lawrence J. ;
Tyrrell, Lynda ;
Black, Joel A. ;
Cummins, Theodore R. ;
Waxman, Stephen G. .
NATURE PROTOCOLS, 2009, 4 (08) :1118-1127