新遗传证据显示精神分裂症不是单一种疾病


  【24drs.com】一篇新研究认为,根据带有新颖或罕见的破坏性变种的一组基因,精神分裂症不是单一种疾病,而是由多种症状的不同亚型组成。
  
  纽约市纽约大学Langone医学中心的研究者表示,他们已在四个有影响力的基因发现突变,与四个不同的精神分裂症表型清楚对映,奠定了迈向更加个人化治疗之基础。与这四种基因突变有关之精神病患者,彼此在症状、智力程度和其它疾病特征方面都有差异。
  
  这篇研究发表于四月的EBioMedicine期刊。
  
  第一作者Dolores Malaspina医师表示,有许多基因被发现会增加精神疾病,包括精神分裂症的易感性。她解释,他们是透过大型的GWASs[genome-wide association studies]研究发现,不过,它们不是很具体。所以,问题是,如何聚焦于可能会更直接影响疾病的基因呢?
  
  NYU Langone精神科名誉教授Malaspina医师在新闻稿中表示,我们的生物学研究促成开始回答在该领域已长期存在的问题,为何任两个诊断有精神分裂者的患者可能有著完全不同的症状?我们首度在机制上定义了四个症候群。
  
  这些研究结果是根据非常良好的特点和不同种族群体的48个精神病患者,对四个中枢神经系统的信号基因进行了目标性的外显子定序,因为这几个基因曾在偶发之精神分裂症案例的新突变中显示有破坏性,这四个基因都与神经回路的生长或调节有关。
  
  48名患者中有15人(31.25%)带有这四个基因之一种或多种的罕见或新型的突变,这几个亚型的患者有明显不同的症状。
  
  其中一个基因是PTPRG (受体型酪氨酸蛋白磷酸酶γ/receptor-type tyrosine-protein phosphatase gamma),其编码的蛋白质让神经细胞连接而构成神经网络。这个基因出现罕见突变的患者,更早发生相对严重的精神病、以及学习障碍史。研究者表示,尽管有一些患者有高智能,她们在操作记忆上表现出认知障碍。
  
  另一个受到影响的基因是SLC39A13 (锌转运蛋白家族39编号13/ zinc transporter family 39 member 13)。这个基因出现罕见突变的患者,也经历了提早发作的精神分裂症,但他们表现出整个打乱的认知和最严重的精神病理,包括负性症状和严重的自杀企图。研究者报告指出,他们有最低的智能和最低教育程度,并有发育障碍。
  
  患者如有第三个受影响的基因ARMS/KIDINS220 (富含锚蛋白重复结构之跨膜蛋白/ankyrin repeat-rich membrane-spanning protein)之变异,显示出早期前景,很多读到大学,然后,他们经历了与退化过程一致的认知能力下降。
  
  患者如有第四个受影响的基因TGM5 (转谷氨酰酶5/transglutaminase 5)之变异,童年时症状较轻,但童年时往往经历了注意力缺陷障碍,且这些患者的处理速度比较慢。
  
  第一作者、NYU Langone博士后研究员Thorsten Kranz博士在发表时表示,我们的研究结果认为,新的治疗方法应该 -同时解决核心精神病-也应聚焦于TGM5案例的处理速度、PTPRG案例的操作记忆、SLC39A13案例的锌增强、ARMS/KIDINS220突变者的神经细胞保护。没有可以对所有患者都有用的治疗,但是可以在某些患者非常有效。
  
  举例来说,对于锌转运蛋白SLC39A13有突变的患者,Malaspina医师表示,在一个锌转运蛋白缺陷的大鼠模式中,补充锌可以补救行为表型,所以我们认为这确实建构了在症候群和特定治疗内对特定实体启动照护的舞台。
  
  Malaspina医师结论表示,当然,还要有更大型的样本验证,但是,根据受影响的基因、可能还有更多种基因,它建构了更佳地定义疾病亚型的舞台,数百种基因巧妙地增加任何数量之精神疾病的可变性。
  
  资料来源:http://www.24drs.com/
  
  Native link:Schizophrenia Not One Disease, New Genetic Evidence Shows

Schizophrenia Not One Disease, New Genetic Evidence Shows

By Megan Brooks
Medscape Medical News

Schizophrenia is not a single disease but rather is a group of distinct subtypes with varying symptoms based on a set of genes harboring novel or rare disruptive variants, a new study suggests.

Researchers from New York University Langone Medical Center, in New York City, say they have uncovered mutations in four "influential" genes that clearly align with four different schizophrenia phenotypes, paving the way toward more personalized treatments. Patients with psychoses associated with mutations in each of the four genes differed from each other with respect to symptoms, intelligence level, and other disease features.

The study was published in the April issue of EBioMedicine.

Genes That Matter

"A large number of genes have been discovered that increase the vulnerability for psychiatric disorders, including schizophrenia," lead author Dolores Malaspina, MD, told Medscape Medical News. "They were found through large GWASs [genome-wide association studies], and they're not very specific. So the question is, how can we zero in on the genes that are likely to influence the disease more directly?" she explained.

"Our biologically driven study begins to answer long-standing questions in the field about why any two people diagnosed with schizophrenia may have drastically different symptoms. For the first time, we have defined four syndromes mechanistically," Dr Malaspina, the Anita Steckler and Joseph Steckler Professor in the Department of Psychiatry at NYU Langone, added in a news release.

The findings are based on an "exceptionally well-characterized" and ethnically diverse group of 48 individuals with psychosis for whom targeted exome sequencing was conducted with regard to four central nervous system signaling genes that have previously been shown to harbor disruptive de novo mutations in sporadic cases of schizophrenia. All four genes are involved in the growth or regulation of nerve circuits.

Fifteen of the 48 patients (31.25%) carried rare or novel variants in one or more of the four genes, and these subgroups of patients had significantly different symptoms.

One gene is PTPRG (receptor-type tyrosine-protein phosphatase gamma), which encodes a protein that allows nerve cells to connect as they form nerve networks. Patients with rare variants in this gene experienced earlier onset of relatively severe psychosis and had a history of learning disabilities. Despite high intelligence in some, they showed cognitive deficits in working memory, the researchers say.

Another influential gene is SLC39A13 (zinc transporter family 39 member 13). Patients with mutations in this gene also experienced early onset of schizophrenia, but they showed globally disrupted cognition and the most severe psychopathology, including negative symptoms and severe suicide attempts. They had the lowest intelligence and the least educational attainment, consistent with a developmental disorder, the researchers report.

Patients with variants in a third influential gene, ARMS/KIDINS220 (ankyrin repeat-rich membrane-spanning protein), showed early promise, and many attended college. They then experienced cognitive decline, consistent with a degenerative process.

Patients with variants in a fourth influential gene, TGM5 (transglutaminase 5), had less severe symptoms but often experienced attention-deficit disorder during childhood, and processing speed was slow in these patients.

Genotype, Then Treat?

"Our results argue that new treatments should ─ while addressing core psychoses ─ also focus on processing speed in TGM5 cases, working memory in PTPRG, zinc augmentation in SLC39A13, and nerve cell protection in patients with ARMS/KIDINS220 mutations," first study author Thorsten Kranz, PhD, a postdoctoral fellow at NYU Langone, said in the release. "Treatments that do not work for all patients may be highly effective in some."

For example, for patients with mutations in the zinc transporter SLC39A13, "there is a mouse model with a defect in this zinc transporter gene that has a behavior phenotype that is rescued by zinc supplementation, so we think this does set the stage to start carving out specific entities within the syndrome and specific treatments," Dr Malaspina told Medscape Medical News.

"Of course, this needs to be replicated in larger samples, but I think it sets the stage to better define the disease subtypes based on influential genes and not just the many, many hundreds of genes that subtly increase the variability for any number of psychiatric disorders," Dr Malaspina concluded.

This research was supported by the National Institutes of Health. The authors have disclosed no relevant financial relationships.

EBioMedicine. 2016;6:206-214.

    
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