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首页> 外文期刊>Neuron >Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors
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Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors

机译：KATNB1突变通过破坏不对称划分的神经祖细胞引起复杂的脑畸形。

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摘要

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.
机译：对2,000多名复杂的皮质发育畸形儿童进行外显子组测序分析，确定KATNB1中有五个独立的（四个纯合子和一个复合杂合子）有害突变，编码微管切割酶Katanin的调节亚基。在源自患者的成纤维细胞中，有丝分裂纺锤体的形成是有缺陷的，这是突变体KATNB1与KATNA1，Katanin的催化亚基以及其他微管相关蛋白相互作用破坏的结果。斑马鱼（katnb1）和果蝇（kat80）中KATNB1直系同源基因的缺失导致小头畸形，重现了人类的表型。在发育中的果蝇视神经叶中，kat80的丢失会特别影响不对称分裂的神经母细胞，在有丝分裂过程中，神经母细胞显示出多余的中心体和纺锤体异常，导致细胞周期进程延迟和细胞数量减少。此外，kat80耗竭会导致感觉和运动神经元的树突状乔化缺陷，从而影响神经结构。综上所述，我们提供了有关KATNB1突变导致人类大脑皮层畸形的机制的见解，证明了其在大脑发育过程中的基本作用。

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