Neuron：鉴别大脑发育关键基因或助开发大脑发育障碍新疗法

  近日，发表在国际杂志Neuron上的一篇研究论文中，来自新加坡A*STAR研究所等处的研究人员鉴别出了一种可以解释人类大脑尺寸的遗传路径，并发现了一种名为 KATNB1的基因，其是该遗传路径中的关键组分，主要负责人类和其它动物中枢神经系统的发育。
  文章中，通过对正常身高但大脑尺寸较小的个体进行全基因组测序研究，研究人员鉴别出了基因KATNB1突变，这就表明该基因对人类大脑适当发育非常关键；头部尺寸较小（小头）是一种和神经发育障碍相关的疾病，通常通过计算婴儿的头围来进行判定。小头一般起源于多种状况，而这些机体状况常常会在怀孕期间或个体出生后的神经变性过程中引发个体大脑的异常生长，最终导致个体头围较小，而一般来讲小头个体由于大脑功能下降也会伴随着预期寿命的缩短。
  随后研究者进行实验来确定KATNB1基因的功能，利用缺失KATNB1基因的模型进行研究，研究人员表示，该基因对于大脑达到正确的尺寸非常关键，而研究中缺失该基因的斑马鱼和小鼠胚胎并不能在某一个特定阶段存活，而且其大脑及头部尺寸明显变小，这类似于在人类中的表现。
  研究者Reversade表示，我们将继续研究其它大脑发育的关键基因，以期待揭示人类大脑进化及其发挥认知能力的分子机制；本文中研究人员发现了对大脑发育的关键基因，为后期进行深入研究以开发治疗大脑发育障碍的靶向性疗法提供了新的思路和策略。（转化医学网360zhyx.com）
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Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors
Neuron doi:10.1016/j.neuron.2014.12.014
Ketu Mishra-Gorur19, Ahmet Okay Çağlayan19, Ashleigh E. Schaffer, Chiswili Chabu, Octavian Henegariu, Fernando Vonhoff, Gözde Tuğce Akgümüş, Sayoko Nishimura, Wenqi Han, Shu Tu, Burçin Baran, Hakan Gümüş, Cengiz Dilber, Maha S. Zaki, Heba A.A. Hossni, Jean-Baptiste Rivière, Hülya Kayserili, Emily G. Spencer, Rasim Ö. Rosti, Jana Schroth, Hüseyin Per, Caner Çağlar, Çağri Çağlar, Duygu Dölen, Jacob F. Baranoski, Sefer Kumandaş, Frank J. Minja, E. Zeynep Erson-Omay, Shrikant M. Mane, Richard P. Lifton, Tian Xu, Haig Keshishian, William B. Dobyns, Neil C. Chi, Nenad Šestan, Angeliki Louvi, Kaya Bilgüvar, Katsuhito Yasuno, Joseph G. Gleeson, Murat Günel
Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development.