Dipartimento Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy.
Genes (Basel). 2021 Jul 14;12(7):1073. doi: 10.3390/genes12071073.
Craniosynostosis (CS) is the second most prevalent inborn craniofacial malformation; it results from the premature fusion of cranial sutures and leads to dimorphisms of variable severity. CS is clinically heterogeneous, as it can be either a sporadic isolated defect, more frequently, or part of a syndromic phenotype with mendelian inheritance. The genetic basis of CS is also extremely heterogeneous, with nearly a hundred genes associated so far, mostly mutated in syndromic forms. Several genes can be categorised within partially overlapping pathways, including those causing defects of the primary cilium. The primary cilium is a cellular antenna serving as a signalling hub implicated in mechanotransduction, housing key molecular signals expressed on the ciliary membrane and in the cilioplasm. This mechanical property mediated by the primary cilium may also represent a cue to understand the pathophysiology of non-syndromic CS. In this review, we aimed to highlight the implication of the primary cilium components and active signalling in CS pathophysiology, dissecting their biological functions in craniofacial development and in suture biomechanics. Through an in-depth revision of the literature and computational annotation of disease-associated genes we categorised 18 ciliary genes involved in CS aetiology. Interestingly, a prevalent implication of midline sutures is observed in CS ciliopathies, possibly explained by the specific neural crest origin of the frontal bone.
颅缝早闭（CS）是第二常见的先天性颅面畸形；它是由于颅骨缝过早融合导致的，导致不同严重程度的畸形。CS 临床表现异质性，因为它既可以是散发性孤立性缺陷，更常见，也可以是孟德尔遗传的综合征表型的一部分。CS 的遗传基础也极其异质性，迄今为止已与近百个基因相关，这些基因主要在综合征形式中发生突变。一些基因可以归类为部分重叠的途径，包括那些导致初级纤毛缺陷的基因。初级纤毛是一种细胞天线，作为一个信号枢纽，参与机械转导，在纤毛膜和纤毛质中表达关键的分子信号。这种由初级纤毛介导的机械特性也可能代表了理解非综合征性 CS 病理生理学的线索。在这篇综述中，我们旨在强调初级纤毛成分和活性信号在 CS 病理生理学中的作用，剖析它们在颅面发育和颅骨缝生物力学中的生物学功能。通过对文献的深入复习和对疾病相关基因的计算注释，我们将 18 个与 CS 发病机制相关的纤毛基因进行了分类。有趣的是，在 CS 纤毛病中观察到中线缝的普遍受累，这可能是由额骨的特定神经嵴起源所解释的。
