A de novo gain-of-function mutation in SCN11A causes loss of pain perception

被引:216
|
作者
Leipold, Enrico [1 ,2 ]
Liebmann, Lutz [3 ]
Korenke, G. Christoph [4 ]
Heinrich, Theresa [3 ]
Giesselmann, Sebastian [3 ]
Baets, Jonathan [5 ,6 ,7 ]
Ebbinghaus, Matthias [8 ]
Goral, R. Oliver [1 ,2 ]
Stodberg, Tommy [9 ]
Hennings, J. Christopher [3 ]
Bergmann, Markus [10 ]
Altmueller, Janine [11 ]
Thiele, Holger [11 ]
Wetzel, Andrea [12 ]
Nuernberg, Peter [11 ,13 ,14 ,15 ]
Timmerman, Vincent [5 ,16 ]
De Jonghe, Peter [5 ,6 ,7 ]
Blum, Robert [12 ]
Schaible, Hans-Georg [8 ]
Weis, Joachim [17 ,18 ]
Heinemann, Stefan H. [1 ,2 ]
Huebner, Christian A. [3 ]
Kurth, Ingo [3 ]
机构
[1] Univ Jena, Dept Biophys, Ctr Mol Biomed, Jena, Germany
[2] Jena Univ Hosp, Jena, Germany
[3] Jena Univ Hosp, Inst Human Genet, Jena, Germany
[4] Oldenburg Hosp, Pediat Ctr, Dept Neuropediat, Oldenburg, Germany
[5] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2020 Antwerp, Belgium
[6] Univ Antwerp VIB, Dept Mol Genet, Neurogenet Grp, B-2610 Antwerp, Belgium
[7] Univ Antwerp Hosp, Dept Neurol, Antwerp, Belgium
[8] Jena Univ Hosp, Inst Physiol, Div Neurophysiol, Jena, Germany
[9] Karolinska Univ Hosp, Dept Neuropediat, Stockholm, Sweden
[10] Hosp Bremen Mitte, Inst Neuropathol, Bremen, Germany
[11] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany
[12] Univ Wurzburg, Inst Clin Neurobiol, D-97070 Wurzburg, Germany
[13] Univ Cologne, Cologne Excellence Cluster Cellular Stress Resp A, D-50931 Cologne, Germany
[14] ATLAS Biolabs, Berlin, Germany
[15] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany
[16] Univ Antwerp VIB, Dept Mol Genet, Peripheral Neuropathy Grp, B-2610 Antwerp, Belgium
[17] RWTH Aachen Univ Hosp, Inst Neuropathol, Aachen, Germany
[18] Julich Aachen Res Alliance JARA Brain Translat Me, Aachen, Germany
关键词
SODIUM-CHANNEL NA(V)1.9; RESISTANT NA+ CURRENT; MOLECULAR-MECHANISMS; AXON GROWTH; NEUROTRANSMISSION; DEPOLARIZATION; TRANSMISSION; EXCITABILITY; NOCICEPTORS; DELETION;
D O I
10.1038/ng.2767
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The sensation of pain protects the body from serious injury(1-3). Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Na(v)1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system(4,5). Mutant Na(v)1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain- of- function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.
引用
收藏
页码:1399 / +
页数:9
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