A missense mutation in Katnal1 underlies behavioural, neurological and ciliary anomalies.
A missense mutation in Katnal1 underlies behavioural, neurological and ciliary anomalies.
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DOI：
10.1038/mp.2017.54
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发表时间：
2018-03
影响因子：
11
通讯作者：
Nolan PM
中科院分区：
文献类型：
--
作者：
Banks G;Lassi G;Hoerder-Suabedissen A;Tinarelli F;Simon MM;Wilcox A;Lau P;Lawson TN;Johnson S;Rutman A;Sweeting M;Chesham JE;Barnard AR;Horner N;Westerberg H;Smith LB;Molnár Z;Hastings MH;Hirst RA;Tucci V;Nolan PM
微管切断酶在整个发育和成年期中实现多种组织特异性分子功能。尽管微管切断是许多动态神经过程的基础，但人们对家族成员 Katanin p60 亚基 A 样 1 (KATNAL1) 在中枢神经系统 (CNS) 功能中的作用知之甚少。最近的研究报告称，人类中包含 KATNAL1 位点的微缺失会导致智力障碍和小头畸形，这表明 KATNAL1 可能在中枢神经系统中发挥着重要作用；然而，此类关联缺乏强调将基因与疾病症状联系起来的潜在机制所需的功能数据。在这里，我们鉴定并表征了 Katnal1 中携带功能缺失等位基因的小鼠品系。我们发现突变体表现出行为缺陷，包括昼夜节律、睡眠、焦虑和学习/记忆。此外，在 Katnal1 突变小鼠的大脑中，我们发现了许多形态异常以及神经元迁移和形态缺陷。此外，我们还证明了突变体的心室室管膜细胞的运动纤毛存在缺陷，这表明 Katnal1 在纤毛功能发育中的作用。我们相信，我们在这里提供的数据是第一个将 KATNAL1 与此类表型联系起来的数据，证明该蛋白质在神经元功能和行为发育不可或缺的许多过程中发挥着关键作用。
Microtubule severing enzymes implement a diverse range of tissue-specific molecular functions throughout development and into adulthood. Although microtubule severing is fundamental to many dynamic neural processes, little is known regarding the role of the family member Katanin p60 subunit A-like 1, KATNAL1, in central nervous system (CNS) function. Recent studies reporting that microdeletions incorporating the KATNAL1 locus in humans result in intellectual disability and microcephaly suggest that KATNAL1 may play a prominent role in the CNS; however, such associations lack the functional data required to highlight potential mechanisms which link the gene to disease symptoms. Here we identify and characterise a mouse line carrying a loss of function allele in Katnal1. We show that mutants express behavioural deficits including in circadian rhythms, sleep, anxiety and learning/memory. Furthermore, in the brains of Katnal1 mutant mice we reveal numerous morphological abnormalities and defects in neuronal migration and morphology. Furthermore we demonstrate defects in the motile cilia of the ventricular ependymal cells of mutants, suggesting a role for Katnal1 in the development of ciliary function. We believe the data we present here are the first to associate KATNAL1 with such phenotypes, demonstrating that the protein plays keys roles in a number of processes integral to the development of neuronal function and behaviour.
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影响因子：
16.6
作者：
Guo J;Higginbotham H;Li J;Nichols J;Hirt J;Ghukasyan V;Anton ES
通讯作者：
Anton ES
影响因子：
2
作者：
Haldeman-Englert, Chad R.;Naeem, Taiyabah;Geiger, Elizabeth A.;Warnock, Ashley;Feret, Holly;Ciano, Melissa;Davidson, Stefanie L.;Deardorff, Matthew A.;Zackai, Elaine H.;Shaikh, Tamim H.
通讯作者：
Shaikh, Tamim H.
影响因子：
3.3
作者：
Glausier, J. R.;Lewis, D. A.
通讯作者：
Lewis, D. A.
影响因子：
4.2
作者：
Banks G;Heise I;Starbuck B;Osborne T;Wisby L;Potter P;Jackson IJ;Foster RG;Peirson SN;Nolan PM
通讯作者：
Nolan PM
影响因子：
1.7
作者：
BELICHENKO, PV;OLDFORS, A;DAHLSTROM, A
通讯作者：
DAHLSTROM, A