英国和澳大利亚研究人员在新一期美国《科学》杂志上报告说，他们发现了一种与“渐冻症”相关的新基因，这将有助于科研人员进一步了解这种致命的运动神经元退行性疾病的发病机理。
“渐冻症”医学名称叫做肌萎缩侧索
硬化症，英文名称简称为ＡＬＳ，其主要临床表现是肌肉逐渐萎缩无力，患者最后会因呼吸衰竭而死亡。这种病被世界卫生组织列为五大绝症之一，著名物理学家霍金就是这种疾病的患者。
来自伦敦大学国王学院等机构的科研人员介绍说，在１９９３年人们曾发现过一个与家族遗传性“渐冻症”发病相关的变异基因ＳＯＤ１，但仅有约１％的患者发病与此有关。这次他们发现的是一个名为ＴＤＰＢ的基因，虽然该基因变异也不多见，但研究发现它的变异与“渐冻症”的病理有比较密切的关联。
在研究中，科研人员选取了１５４名患有家族性“渐冻症”、但并没有ＳＯＤ１变异基因的患者为研究对象。结果在其中一个家族的４位患者身上发现了一种相同的碱基变异，位于ＴＤＰＢ基因上。而且在“渐冻症”患者体内发生病变的神经元中，科研人员发现由这个基因变异后编码的ＴＤＰ－４３蛋白质均形成团簇状堆积。
为了验证ＴＤＰＢ基因变异是否也与非家族性“渐冻症”有关，研究人员又在英国和澳大利亚分别选取了２００名和１７２名非家族性“渐冻症”患者，对其体内的ＴＤＰＢ基因进行测序。结果发现，至少有两人体内存在ＴＤＰＢ基因其他形式的变异。而在１２００多名健康的对照者体内，没有一个人被发现携带该基因的变异。
研究项目负责人克里斯托弗·肖说，能够发现同一个基因的多种变异形式是“极其罕见的”。而且，这些变异形式似乎有着相同的影响。在实验中，他们培育体内ＴＤＰＢ基因变异的鸡，发现鸡的一些神经元及其他细胞会死亡。研究小组计划下一步把变异的ＴＤＰＢ基因植入老鼠体内，以观察该基因变异能否导致哺乳动物体内的神经元死亡。
New Gene Nailed for ALS
By Devin Powell
ScienceNOW Daily News
28 February 2008
生物谷推荐原文阅读：
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.
