在期刊Journal of Clinical Investigation上,，一個(gè)國(guó)際科學(xué)家小組,，由劍橋大學(xué)Evan Reid博士和邁阿密大學(xué)Stephan Zuchner博士所領(lǐng)導(dǎo),，報(bào)道了基因reticulon2突變導(dǎo)致一種遺傳性痙攣性截癱（HSP）,，該基因位于染色體19上。HSP以腿進(jìn)展性強(qiáng)直和攣縮為特點(diǎn),，由軸突的選擇性和特異性變性所造成,。
該小組在基因reticulon2上確定了三個(gè)突變作為一種HSP的病因--在其中一個(gè)病例中,，這種突變包括整個(gè)基因的刪除。此外,，研究人員還指出基因reticulon2與另一個(gè)基因spastin相互作用,。這個(gè)基因的突變引起最常見(jiàn)的遺傳性痙攣性截癱,。
reticulon2基因編碼一個(gè)漿膜蛋白（reticulon protein），此蛋白是一個(gè)蛋白質(zhì)家族中的一員,，在內(nèi)質(zhì)網(wǎng)成形中起關(guān)鍵作用,。內(nèi)質(zhì)網(wǎng)是一個(gè)相互連接的膜和小管的網(wǎng)絡(luò)系統(tǒng)，延伸至幾乎所有細(xì)胞中的整個(gè)細(xì)胞質(zhì),。
內(nèi)質(zhì)網(wǎng)有幾種功能,，包括蛋白質(zhì)合成,、鈣信號(hào)和細(xì)胞其他組成部分的調(diào)節(jié),。最近的數(shù)據(jù)表明,，膜是參與蛋白質(zhì)合成，而管是專(zhuān)門(mén)用來(lái)執(zhí)行其他功能,。
這項(xiàng)新研究提供了目前最直接的證據(jù),，內(nèi)質(zhì)網(wǎng)如何成形和形成的缺陷可能是軸突變性的基礎(chǔ)。當(dāng)軸突退化,，信號(hào)無(wú)法通過(guò)神經(jīng)細(xì)胞,，導(dǎo)致中樞神經(jīng)系統(tǒng)內(nèi)溝通崩潰。這在神經(jīng)系統(tǒng)變性疾病中是常見(jiàn)的,，如多發(fā)性硬化癥,。
"我們的工作突出了重要的新疾病機(jī)制，這可為我們研究軸突在諸如HSP樣的毀滅性疾病中如何受損提供了一個(gè)平臺(tái),，甚至是在多發(fā)性硬化癥中,，此病在某些情況下與HSP非常相似"， Reid博士這樣解釋?zhuān)且粋€(gè)韋爾科姆基金會(huì)臨床科學(xué)上的高級(jí)研究員,，"但我們一定不能忘記這項(xiàng)工作可能立即直接有利于受HSP影響的家庭,，此發(fā)現(xiàn)為他們開(kāi)辟了遺傳咨詢和檢測(cè)的可能性"。（生物谷bioon.com）
doi:doi:10.1172/JCI60560
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Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12
Gladys Montenegro, Adriana P. Rebelo, James Connell, Rachel Allison,Carla Babalini, Michela D'Aloia, Pasqua Montieri, Rebecca Schüle, Hiroyuki Ishiura,Justin Price, Alleene Strickland, Michael A. Gonzalez, Lisa Baumbach-Reardon,Tine Deconinck, Jia Huang, Giorgio Bernardi, Jeffery M. Vance, Mark T. Rogers,Shoji Tsuji, Peter De Jonghe, Margaret A. Pericak-Vance, Ludger Sch?ls, Antonio Orlacchio, Evan Reid and Stephan Züchner
Abstract Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules - receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) - have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER. RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP.
