Intracerebral calcium deposition, classified into primary familial brain calcification (PFBC) and secondary brain calcification, occurs within the brain parenchyma and vasculature. PFBC manifests with progressive motor decline, dysarthria, and cognitive impairment, with limited treatment options available. Recent research has suggested a link between dysfunction of the blood–brain barrier (BBB) and PFBC, with certain genetic variants potentially affecting neurovascular unit (NVU) function, thereby contributing to BBB integrity disruption and brain calcification. Cell junctions play an indispensable role in maintaining the function of NVUs. The pathogenic mechanisms of PFBC‐causative genes, such as PDGFRB, PDGFB, MYORG, and JAM2, involve NVU disruption. Cell junctions, such as tight junctions, gap junctions, adherens junctions, desmosomes, hemidesmosomes, and focal adhesions, are vital for cell–cell and cell–extracellular matrix connections, maintaining barrier function, cell adhesion, and facilitating ion and metabolite exchange. Several recent studies have highlighted the role of mutations in genes encoding cell junction proteins in the onset and progression of brain calcification and its related phenotypes. This emerging body of research offers a unique perspective for investigating the underlying mechanisms driving brain calcification. In this review, we conducted an examination of the literature reporting on genetic variants in cell junction proteins associated with brain calcification to delineate potential molecular pathways and investigate genotype–phenotype correlations. This approach not only reinforces the rationale for molecular subtyping of brain calcification but also lays the groundwork for the discovery of novel causative genes involved in pathogenesis. © 2024 International Parkinson and Movement Disorder Society.

中文翻译：

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与脑钙化相关的细胞连接蛋白的基因突变


脑内钙沉积分为原发性家族性脑钙化 （PFBC） 和继发性脑钙化，发生在脑实质和脉管系统内。PFBC 表现为进行性运动能力下降、构音障碍和认知障碍，可用的治疗选择有限。最近的研究表明，血脑屏障 （BBB） 功能障碍与 PFBC 之间存在联系，某些遗传变异可能影响神经血管单位 （NVU） 功能，从而导致 BBB 完整性破坏和脑钙化。细胞连接在维持 NVU 的功能方面起着不可或缺的作用。PFBC 致病基因（如 PDGFRB、PDGFB、MYORG 和 JAM2）的致病机制涉及 NVU 破坏。细胞连接，如紧密连接、间隙连接、粘附连接、桥粒、半桥粒和黏着斑，对于细胞间和细胞间细胞外基质连接至关重要，可维持屏障功能、细胞粘附并促进离子和代谢物交换。最近的几项研究强调了编码细胞连接蛋白的基因突变在脑钙化及其相关表型的发生和进展中的作用。这一新兴的研究机构为研究驱动脑钙化的潜在机制提供了独特的视角。在这篇综述中，我们对报道与脑钙化相关的细胞连接蛋白遗传变异的文献进行了检查，以描绘潜在的分子途径并研究基因型-表型相关性。这种方法不仅加强了脑钙化分子亚型的基本原理，而且为发现参与发病机制的新致病基因奠定了基础。 © 2024 年国际帕金森和运动障碍协会。