Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder.
Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder.
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Bi-callialic CAMSAP1变体引起临床上可识别的神经元迁移障碍。
DOI：
10.1016/j.ajhg.2022.09.012
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发表时间：
2022-11-03
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
非中心体微管是神经元轴突形成、轴突运输和神经元迁移过程中必不可少的细胞骨架丝。它们需要通过微管负端靶向蛋白（包括CAMSAP分子家族）来稳定。使用外显子组测序的样品从五个不相关的家庭，我们表明，双等位基因CAMSAP 1功能丧失的变体导致临床上可识别的，综合征性神经元迁移障碍。该综合征的主要临床特征包括特征性颅面外观、原发性小头畸形、严重的神经发育迟缓、皮质性视觉障碍和癫痫发作。神经放射学表型包括一个高度可识别的典型无脑回畸形组合，后部比前部梯度更严重，类似于PAFAH 1B 1（LIS 1）相关的无脑回畸形和严重发育不全或胼胝体缺失;基底节、海马和中脑发育不良;小脑发育不全，类似于微管蛋白病，一组单基因微管蛋白相关的皮质发育不良疾病。来自受影响个体的神经细胞玫瑰花结谱系显示与这些表型一致的结果，包括异常形态、细胞增殖减少和神经元分化。Camsap 1基因敲除小鼠显示围产期死亡率增加，RNAScope研究发现，在整个神经发生过程中大脑和面部结构中的表达水平较高，与小鼠和人类神经发育和颅面表型一致。我们的研究结果共同证实了CAMSAP 1在神经元迁移和大脑发育中的基本作用，并将双等位基因变体定义为人类和小鼠临床上不同的神经发育障碍的原因。我们描述了CAMSAP 1的双等位基因变体，CAMSAP 1编码一种对负端微管稳定至关重要的分子，作为临床可识别的综合征性神经元迁移障碍的原因，与“微管蛋白病”相似。Camsap 1 −/−小鼠显示围产期死亡率增加，先证者来源的神经细胞花环谱系显示细胞增殖和分化减少。
Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice. We describe bi-allelic variants in CAMSAP1, which encodes a molecule crucially important for minus-end microtubule stabilization, as a cause of a clinically recognizable, syndromic neuronal migration disorder with similarities to the “tubulinopathies.” Camsap1−/− mice displayed increased perinatal mortality, and proband-derived neural cell rosette lineages showed decreased cell proliferation and differentiation.
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影响因子：
11.2
作者：
Desikan, Rahul S.;Barkovich, A. James
通讯作者：
Barkovich, A. James
影响因子：
3.3
作者：
Splinter D;Razafsky DS;Schlager MA;Serra-Marques A;Grigoriev I;Demmers J;Keijzer N;Jiang K;Poser I;Hyman AA;Hoogenraad CC;King SJ;Akhmanova A
通讯作者：
Akhmanova A
影响因子：
10.7
作者：
Baines, Anthony J.;Bignone, Paola A.;Phillips, Gareth W.
通讯作者：
Phillips, Gareth W.
影响因子：
11.8
作者：
Jiang, Kai;Hua, Shasha;Akhmanova, Anna
通讯作者：
Akhmanova, Anna
DOI：
10.1073/pnas.1404133111
发表时间：
2014-04-22
影响因子：
11.1
作者：
Hendershott, Melissa C.;Vale, Ronald D.
通讯作者：
Vale, Ronald D.