Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development.
Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development.
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DOI：
10.1007/s12311-022-01379-3
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发表时间：
2023-04
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影响因子：
--
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中科院分区：
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小脑发育不全和发育不良包括一组临床和遗传异质性疾病，经常与神经发育障碍。神经元导航器2（NAV 2）基因（MIM：607，026）编码神经元导航器蛋白家族的成员，其在中枢神经系统（CNS）内广泛表达，并且在发育中的小脑中特别丰富。不同物种的证据支持NAV 2在细胞骨架动力学和神经突生长中的关键功能。具体地，小鼠中Nav2的缺乏导致小脑发育不全，由于受损的轴突生长而具有异常的叶状。然而，关于NAV 2基因在人类疾病表型中的参与知之甚少。在这项研究中，我们发现了一名患有神经发育障碍和复杂的大脑和心脏畸形的女性，其中临床外显子组测序导致鉴定出NAV 2双等位基因截短变体。通过对患者来源的成纤维细胞进行蛋白质表达分析和细胞迁移测定，我们提供了将NAV 2缺陷与细胞迁移缺陷联系起来的证据。在模型生物中，Nav2亚形态小鼠的总体CNS组织病理学显示发育异常，包括小脑发育不全和发育不良、胼胝体发育不全和嗅球发育不全。最后，我们表明，NAV2的直系同源果蝇，sickie（生病）是广泛表达的苍蝇的大脑，生病的突变体大多是致命的幸存者表现出神经行为表型的逃生。总之，我们的研究结果揭示了一种新的人类神经发育障碍，由于遗传丢失的NAV 2，突出了关键保守的作用，NAV 2基因在大脑和小脑发育跨物种。在线版本包含补充材料，可通过10.1007/s12311 - 022 - 01379 - 3获得。
Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. In this study, we identified a female affected with neurodevelopmental impairment and a complex brain and cardiac malformations in which clinical exome sequencing led to the identification of NAV2 biallelic truncating variants. Through protein expression analysis and cell migration assay in patient-derived fibroblasts, we provide evidence linking NAV2 deficiency to cellular migration deficits. In model organisms, the overall CNS histopathology of the Nav2 hypomorphic mouse revealed developmental anomalies including cerebellar hypoplasia and dysplasia, corpus callosum hypo-dysgenesis, and agenesis of the olfactory bulbs. Lastly, we show that the NAV2 ortholog in Drosophila, sickie (sick) is widely expressed in the fly brain, and sick mutants are mostly lethal with surviving escapers showing neurobehavioral phenotypes. In summary, our results unveil a novel human neurodevelopmental disorder due to genetic loss of NAV2, highlighting a critical conserved role of the NAV2 gene in brain and cerebellar development across species. The online version contains supplementary material available at 10.1007/s12311-022-01379-3.
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影响因子：
7.7
作者：
Lee PT;Zirin J;Kanca O;Lin WW;Schulze KL;Li-Kroeger D;Tao R;Devereaux C;Hu Y;Chung V;Fang Y;He Y;Pan H;Ge M;Zuo Z;Housden BE;Mohr SE;Yamamoto S;Levis RW;Spradling AC;Perrimon N;Bellen HJ
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Bellen HJ
影响因子：
7.7
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Li F;Lindsey JW;Marin EC;Otto N;Dreher M;Dempsey G;Stark I;Bates AS;Pleijzier MW;Schlegel P;Nern A;Takemura SY;Eckstein N;Yang T;Francis A;Braun A;Parekh R;Costa M;Scheffer LK;Aso Y;Jefferis GS;Abbott LF;Litwin-Kumar A;Waddell S;Rubin GM
通讯作者：
Rubin GM
影响因子：
4.6
作者：
Hsu, Cynthia T.;Bhandawat, Vikas
通讯作者：
Bhandawat, Vikas
影响因子：
9.8
作者：
Goodman, Lindsey D.;Cope, Heidi;Tan, Queenie K-G
通讯作者：
Tan, Queenie K-G
影响因子：
3.5
作者：
Koziol, Leonard F.;Budding, Deborah;Andreasen, Nancy;D'Arrigo, Stefano;Bulgheroni, Sara;Imamizu, Hiroshi;Ito, Masao;Manto, Mario;Marvel, Cherie;Parker, Krystal;Pezzulo, Giovanni;Ramnani, Narender;Riva, Daria;Schmahmann, Jeremy;Vandervert, Larry;Yamazaki, Tadashi
通讯作者：
Yamazaki, Tadashi