英國(guó)和澳大利亞研究人員在新一期美國(guó)《科學(xué)》雜志上報(bào)告說(shuō),，他們發(fā)現(xiàn)了一種與“漸凍癥”相關(guān)的新基因,，這將有助于科研人員進(jìn)一步了解這種致命的運(yùn)動(dòng)神經(jīng)元退行性疾病的發(fā)病機(jī)理。
“漸凍癥”醫(yī)學(xué)名稱(chēng)叫做肌萎縮側(cè)索
硬化癥,，英文名稱(chēng)簡(jiǎn)稱(chēng)為ＡＬＳ,，其主要臨床表現(xiàn)是肌肉逐漸萎縮無(wú)力，患者最后會(huì)因呼吸衰竭而死亡,。這種病被世界衛(wèi)生組織列為五大絕癥之一,，著名物理學(xué)家霍金就是這種疾病的患者,。
來(lái)自倫敦大學(xué)國(guó)王學(xué)院等機(jī)構(gòu)的科研人員介紹說(shuō)，在１９９３年人們?cè)l(fā)現(xiàn)過(guò)一個(gè)與家族遺傳性“漸凍癥”發(fā)病相關(guān)的變異基因ＳＯＤ１,，但僅有約１％的患者發(fā)病與此有關(guān),。這次他們發(fā)現(xiàn)的是一個(gè)名為ＴＤＰＢ的基因，雖然該基因變異也不多見(jiàn),，但研究發(fā)現(xiàn)它的變異與“漸凍癥”的病理有比較密切的關(guān)聯(lián),。
在研究中，科研人員選取了１５４名患有家族性“漸凍癥”,、但并沒(méi)有ＳＯＤ１變異基因的患者為研究對(duì)象,。結(jié)果在其中一個(gè)家族的４位患者身上發(fā)現(xiàn)了一種相同的堿基變異，位于ＴＤＰＢ基因上,。而且在“漸凍癥”患者體內(nèi)發(fā)生病變的神經(jīng)元中,，科研人員發(fā)現(xiàn)由這個(gè)基因變異后編碼的ＴＤＰ－４３蛋白質(zhì)均形成團(tuán)簇狀堆積。
為了驗(yàn)證ＴＤＰＢ基因變異是否也與非家族性“漸凍癥”有關(guān),，研究人員又在英國(guó)和澳大利亞分別選取了２００名和１７２名非家族性“漸凍癥”患者,，對(duì)其體內(nèi)的ＴＤＰＢ基因進(jìn)行測(cè)序。結(jié)果發(fā)現(xiàn),，至少有兩人體內(nèi)存在ＴＤＰＢ基因其他形式的變異,。而在１２００多名健康的對(duì)照者體內(nèi),，沒(méi)有一個(gè)人被發(fā)現(xiàn)攜帶該基因的變異,。
研究項(xiàng)目負(fù)責(zé)人克里斯托弗·肖說(shuō)，能夠發(fā)現(xiàn)同一個(gè)基因的多種變異形式是“極其罕見(jiàn)的”,。而且,，這些變異形式似乎有著相同的影響。在實(shí)驗(yàn)中,，他們培育體內(nèi)ＴＤＰＢ基因變異的雞,，發(fā)現(xiàn)雞的一些神經(jīng)元及其他細(xì)胞會(huì)死亡。研究小組計(jì)劃下一步把變異的ＴＤＰＢ基因植入老鼠體內(nèi),，以觀察該基因變異能否導(dǎo)致哺乳動(dòng)物體內(nèi)的神經(jīng)元死亡,。
New Gene Nailed for ALS
By Devin Powell
ScienceNOW Daily News
28 February 2008
生物谷推薦原文閱讀：
New Gene Nailed for ALS
Even with the entire human genome in hand, scientists can still have trouble rooting out the genes behind a disease. Consider amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. One ALS-related gene mutation was found in 1993, but it affects only 1% of all ALS patients. Now, after a long dry spell, researchers have finally hit on a second. It's just as rare as the first, but it seems to be more closely related to aspects of ALS pathology found in all patients.
ALS typically appears in middle age, slowly destroying the motor neurons used to control muscles and usually killing a patient within 5 years of diagnosis. Five percent of all adult-onset ALS cases are known to have a strong genetic component, affecting multiple family members. But the rest seem to appear spontaneously in people with no prior family history. Scientists know little about what causes these sporadic cases. And the one known ALS gene in inherited ALS, called SOD1, doesn't seem to lead to neuronal death--the primary characteristic of ALS--so the link between this gene and the disease is still unclear.
Christopher Shaw, a neurologist at King's College London, started hunting for other ALS genes by recruiting patients who have the inherited form of the disease but not the SOD1 mutation. While screening 154 people with familial ALS, Shaw and his colleagues found four individuals in one family who shared the same mutation: a single changed base on chromosome 1. The base was located in the TDPB gene, which encodes a protein called TDP-43 whose function isn't clear. In 2006, scientists reported that in both inherited and sporadic ALS, this protein disappears from the nucleus and clumps up in the cytoplasm of brain and motor neurons.
To see whether TDPB might have a role beyond inherited ALS, Shaw's team sequenced the TDPB gene in 200 people from the United Kingdom and 172 from Australia with the sporadic form of the disease. They found two more people with different mutations in the same gene and didn't see it in more than 1200 people without ALS. Finding multiple mutations in the same gene is "pretty rare," says Shaw. All the mutations seem to have the same effect; they alter the part of the TDP-43 protein that interacts with other proteins, the group reports online today in Science. And when they created chicken embryos with a mutated TDPB gene, they found that some neurons and other cells died.
Shaw's next step is to insert this faulty TDPB gene into mice and see if it kills neurons in mammals. Brian Dickie, director of research development at the Motor Neurone Disease Association in Northampton, U.K., believes that these mouse models may offer other insights into ALS, too. "TDP-43 is also deposited in the neurons of people who have dementia," he says, "and, in a small number of ALS cases, dementia precedes loss of motor function." He wonders if Shaw's work will provide a better understanding not only of ALS mechanisms but also of common pathways between ALS and other neurologic diseases.
