生物谷报道：阵发性剧痛症（PEPD）是一种罕见的症状为无征兆性烧灼痛的遗传性疾病，特征是直肠、眼睛和颚部的突发性阵痛。伦敦大学学院的R. Mark Gardiner及其同事在2006年12月7日的Neuron杂志（Cell 出版社）上发表的文章称定位了该病的遗传基础，即外周神经细胞的上的孔样钠通道特异性突变。这种钠通道属于所谓的“电压门控钠通道”，后者在神经元传递神经冲动中起到十分重要的作用。其原理是，神经冲动引发神经细胞中电压差的改变，使得这类通道在瞬间相应打开，钠离子穿过细胞膜，从而进一步引发神经冲动。迅速、精确的激活与失活是它们正常“工作”的关键。
为了弄清PEDP的发病基础，研究者先是详细比较一个有此类遗传性疾病的大家族中发病者与未发病者的遗传特征，发现决定某特殊钠通道上的某成分的名为SCN9A的基因发生了有害突变，而这种突变很可能就是该疾病的罪魁祸首。进一步对11个遗传性发病的家族和2例散发病例的研究确实表明，SCN9A的突变是至少2/3PEPD病人发病的原因。对这些突变的分析揭示，它们妨碍了这种钠通道的快速关闭功能，延长了该通道相关的外周神经细胞的激活。卡马西平在神经细胞培养实验中能纠正这种通道异常，而这种药证实是众所周知的治疗PEPD有效的药物。研究者还将PEPD和另一种卡马西平治疗无效的遗传性疼痛病——原发性肢痛病（PE）进行了比较。后者也是SCN9A突变引起的，特征是运动或温度改变触发的肢端疼痛。PEPD中的突变是妨碍了钠通道的失活，而PE则正好相反 ，是降低了激活的阈值。
该项发现不仅进一步强调了这种钠通道在人类炎性疼痛中的地位，从而可能会引发对其正常功能的深入研究，还解释了PEPD和PE不同的药物敏感性的原因。
Figure 2. Mutations in the SCN9A Gene Underlie Familial Rectal Pain
(A) Diagram summarizing the nature and position of eight mutations within Nav1.7. Text colors: black, R996C mutation (families 4 and 12); purple, V1298F (family 15); pink, V1298D (proband only, family 12); brown, V1299F (family 11); red, I1461T (family 1); orange, F1462V (sporadic case, family 9); blue, T1464I (family 7); green, M1627K (sporadic case, family 8).
(B) Sodium channel amino acid alignments. The human Nav1.7 sodium channel (hNav1.7) amino acid sequence for the four distinct regions surrounding the eight PEPD missense mutations is compared with other human sodium channels (hNav1.1–1.9); mouse and rat Nav1.7, and ancestral sodium channels from fruit fly and jellyfish. (Bi) Lack of conservation of the arginine residue at position 996. By contrast the other seven mutations alter highly conserved amino acids. (Bii) Complete conservation of valine residues at positions 1298 and 1299. (Biii) High degree of conservation of the IFM amino acid motif, which forms the inactivation gate and includes the residues I1461 and F1462, and of the adjacent threonine at position 1464. (Biv) Conservation of methionine at position 1627. The colored triangles indicating the positions of the mutated residues correspond to the colors used in (A) above.
原文出处：
Neuron December 7, 2006: 52 (5)
SCN9A Mutations in Paroxysmal Extreme Pain Disorder: Allelic Variants Underlie Distinct Channel Defects and Phenotypes
Caroline R. Fertleman, Mark D. Baker, Keith A. Parker, Sarah Moffatt, Frances V. Elmslie, Bjarke Abrahamsen, Johan Ostman, Norbert Klugbauer, John N. Wood, R. Mark Gardiner, and Michele Rees
[Summary] [Full Text] [PDF] [Supplemental Data]
相关基因：
SCN9A
Official Symbol: SCN9A and Name: sodium channel, voltage-gated, type IX, alpha [Homo sapiens]
Other Aliases: ETHA, NE-NA, NENA, Nav1.7, PN1
Other Designations: sodium channel, voltage-gated, type IX, alpha polypeptide; voltage-gated sodium channel alpha subunit Nav1.7
Chromosome: 2; Location: 2q24
MIM: 603415
GeneID: 6335
