细胞粘附分子是主要在中枢神经系统中沿着主要轴突途径表达的膜结合蛋白,在神经系统发育中起关键作用。神经细胞分化和迁移,轴突生长和指导,髓鞘形成,和突触形成。这里,我们描述了10个受影响的个体,在神经元细胞粘附分子NRCAM中具有双等位基因变异,导致不同严重程度的神经发育综合征;这些个体来自8个家庭。这种综合征的特征是发育迟缓/智力障碍,低张力,周围神经病变,和/或痉挛。NRCAM变体的计算分析,其中许多聚集在第三纤连蛋白III型(Fn-III)结构域中,强烈建议对NRCAM结构和功能产生有害影响,包括可能破坏其与其他蛋白质的相互作用。先前对小鼠Nrcam缺陷细胞的体外研究证实了这些发现,显示出异常的神经突生长,突触发生,并在有髓鞘的轴突上形成Ranvier节。我们对缺乏第三个Fn-III结构域的斑马鱼nrcamaΔ突变体的研究表明,与野生型幼虫相比,突变幼虫的游泳行为显着改变(p<0.03)。此外,nrcamaΔ突变体在背侧端脑中显示出α-微管蛋白纤维数量增加的趋势,显示白质束和突起的改变。一起来看,我们的研究提供了证据,表明NRCAM破坏可导致一种可变形式的神经发育障碍,并拓宽了对细胞粘附分子家族在神经系统中日益重要的作用的认识.
Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, myelination, and synapse formation. Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. Computational analyses of NRCAM variants, many of which cluster in the third fibronectin type III (Fn-III) domain, strongly suggest a deleterious effect on NRCAM structure and function, including possible disruption of its interactions with other proteins. These findings are corroborated by previous in vitro studies of murine Nrcam-deficient cells, revealing abnormal neurite outgrowth, synaptogenesis, and formation of nodes of Ranvier on myelinated axons. Our studies on zebrafish nrcamaΔ mutants lacking the third Fn-III domain revealed that mutant larvae displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03). Moreover, nrcamaΔ mutants displayed a trend toward increased amounts of α-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections. Taken together, our study provides evidence that NRCAM disruption causes a variable form of a neurodevelopmental disorder and broadens the knowledge on the growing role of the cell adhesion molecule family in the nervous system.