生物谷報(bào)道：陣發(fā)性劇痛癥（PEPD）是一種罕見(jiàn)的癥狀為無(wú)征兆性燒灼痛的遺傳性疾病，特征是直腸,、眼睛和顎部的突發(fā)性陣痛。倫敦大學(xué)學(xué)院的R. Mark Gardiner及其同事在2006年12月7日的Neuron雜志（Cell 出版社）上發(fā)表的文章稱定位了該病的遺傳基礎(chǔ)，即外周神經(jīng)細(xì)胞的上的孔樣鈉通道特異性突變,。這種鈉通道屬于所謂的“電壓門控鈉通道”,，后者在神經(jīng)元傳遞神經(jīng)沖動(dòng)中起到十分重要的作用。其原理是,，神經(jīng)沖動(dòng)引發(fā)神經(jīng)細(xì)胞中電壓差的改變,，使得這類通道在瞬間相應(yīng)打開(kāi)，鈉離子穿過(guò)細(xì)胞膜,，從而進(jìn)一步引發(fā)神經(jīng)沖動(dòng),。迅速、精確的激活與失活是它們正常“工作”的關(guān)鍵,。
為了弄清PEDP的發(fā)病基礎(chǔ),，研究者先是詳細(xì)比較一個(gè)有此類遺傳性疾病的大家族中發(fā)病者與未發(fā)病者的遺傳特征，發(fā)現(xiàn)決定某特殊鈉通道上的某成分的名為SCN9A的基因發(fā)生了有害突變,，而這種突變很可能就是該疾病的罪魁禍?zhǔn)?。進(jìn)一步對(duì)11個(gè)遺傳性發(fā)病的家族和2例散發(fā)病例的研究確實(shí)表明，SCN9A的突變是至少2/3PEPD病人發(fā)病的原因,。對(duì)這些突變的分析揭示,，它們妨礙了這種鈉通道的快速關(guān)閉功能，延長(zhǎng)了該通道相關(guān)的外周神經(jīng)細(xì)胞的激活,?？R西平在神經(jīng)細(xì)胞培養(yǎng)實(shí)驗(yàn)中能糾正這種通道異常，而這種藥證實(shí)是眾所周知的治療PEPD有效的藥物,。研究者還將PEPD和另一種卡馬西平治療無(wú)效的遺傳性疼痛病——原發(fā)性肢痛?。≒E）進(jìn)行了比較。后者也是SCN9A突變引起的,，特征是運(yùn)動(dòng)或溫度改變觸發(fā)的肢端疼痛,。PEPD中的突變是妨礙了鈉通道的失活，而PE則正好相反 ,，是降低了激活的閾值,。
該項(xiàng)發(fā)現(xiàn)不僅進(jìn)一步強(qiáng)調(diào)了這種鈉通道在人類炎性疼痛中的地位，從而可能會(huì)引發(fā)對(duì)其正常功能的深入研究,，還解釋了PEPD和PE不同的藥物敏感性的原因,。
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.
原文出處：
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]
相關(guān)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
